Devices and methods for monitoring non-invasive vagus nerve stimulation

ABSTRACT

Devices and methods are disclosed that treat a medical condition, such as migraine headache, by electrically stimulating a nerve noninvasively, which may be a vagus nerve situated within a patient&#39;s neck. Preferred embodiments allow a patient to self-treat his or her condition. Disclosed methods assure that the device is being positioned correctly on the neck and that the amplitude and other parameters of the stimulation actually stimulate the vagus nerve with a therapeutic waveform. Those methods comprise measuring properties of the patient&#39;s larynx, pupil diameters, blood flow within an eye, electrodermal activity and/or heart rate variability.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. Nonprovisionalapplication Ser. No. 15/018,805 filed Feb. 8, 2016, which is adivisional of U.S. Nonprovisional application Ser. No. 13/872,116 filedApr. 28, 2013 now U.S. Pat. No. 9,254,383 issued Feb. 9, 2016, which isa continuation-in-part of U.S. Nonprovisional application Ser. No.13/858,114 filed Apr. 8, 2013 now U.S. Pat. No. 9,248,286 issued Feb. 2,2016, which (1) claims the benefit of U.S. Provisional Application Ser.No. 61/752,895 filed Jan. 15, 2013, and (2) is a continuation-in-part ofU.S. Nonprovisional application Ser. No. 13/603,799 filed Sep. 5, 2012now U.S. Pat. No. 8,918,178 issued Dec. 23, 2014, which (a) is acontinuation-in-part of U.S. Nonprovisional application Ser. No.13/279,437 filed Oct. 24, 2011 now U.S. Pat. No. 9,174,045 issued Nov.3, 2015, and (b) is a continuation-in-part of U.S. NonprovisionalApplication Ser. No. 13/222,087 filed Aug. 31, 2011 now U.S. Pat. No.9,174,066 issued Nov. 3, 2015, which is a continuation-in-part of U.S.Nonprovisional application Ser. No. 13/183,765 filed Jul. 15, 2011 nowU.S. Pat. No. 8,874,227 issued Mar. 18, 2014, which (i) claims thebenefit of priority of U.S. Provisional Application Ser. No. 61/488,208filed May 20, 2011, and (ii) is a continuation-in-part of U.S.Nonprovisional application Ser. No. 13/183,721 filed Jul. 15, 2011 nowU.S. Pat. No. 8,676,324 issued Mar. 18, 2014, which (A) claims thebenefit of priority of U.S. Provisional Application Ser. No. 61/487,439filed May 18, 2011, and (B) is a continuation-in-part of U.S.Nonprovisional application Ser. No. 13/109,250 filed May 17, 2011 nowU.S. Pat. No. 8,676,330, issued Mar. 18, 2014, which (I) claims thebenefit of priority of U.S. Provisional Application Ser. No. 61/471,405filed Apr. 4, 2011, and (II) is a continuation-in-part of U.S.Nonprovisional application Ser. No. 13/075,746 filed Mar. 30, 2011 nowU.S. Pat. No. 8,874,205 issued Oct. 28, 2014, which 1) claims thebenefit of priority of U.S. Provisional Application 61/451,259 filedMar. 10, 2011, and 2) is a continuation-in-part of U.S. Nonprovisionalapplication Ser. No. 13/005,005 filed Jan. 12, 2011 now U.S. Pat. No.8,868,177 issued Oct. 21, 2014, which is a continuation-in-part of U.S.Nonprovisional application Ser. No. 12/964,050 filed Dec. 9, 2010, whicha) claims the benefit of priority of U.S. Provisional Application Ser.No. 61/415,469 filed Nov. 19, 2010, and b) is a continuation-in-part ofU.S. Nonprovisional Application Ser. No. 12/859,568 filed Aug. 19, 2010now U.S. Pat. No. 9,037,247 issued May 19, 2015, which i) is acontinuation-in-part application of U.S. Nonprovisional Application Ser.No. 12/612,177 filed Nov. 4, 2009 now U.S. Pat. No. 8,041,428 issuedOct. 18, 2011, and ii) is a continuation-in-part of U.S. Nonprovisionalapplication Ser. No. 12/408,131 filed Mar. 20, 2009 now U.S. Pat. No.8,812,112 issued Aug. 19, 2014; each of which is incorporated herein byreference in its entirety.

BACKGROUND OF THE INVENTION

The field of the present invention relates to the delivery of energyimpulses (and/or fields) to bodily tissues for therapeutic purposes, forexample, for treating medical conditions such as migraine headaches. Theenergy impulses (and/or fields) that are used to treat such conditionscomprise electrical and/or electromagnetic energy, deliverednon-invasively to the patient, particularly to a vagus nerve of thepatient. During the course of such treatment, a caregiver and/or thepatient uses the disclosed devices and methods to monitor whether thetreatment is being applied safely and effectively.

The use of electrical stimulation for treatment of medical conditions iswell known. One of the most successful applications of modernunderstanding of the electrophysiological relationship between muscleand nerves is the cardiac pacemaker. Although origins of the cardiacpacemaker extend back into the 1800's, it was not until 1950 that thefirst practical, albeit external and bulky, pacemaker was developed. Thefirst truly functional, wearable pacemaker appeared in 1957, and in1960, the first fully implantable pacemaker was developed.

Around this time, it was also found that electrical leads could beconnected to the heart through veins, which eliminated the need to openthe chest cavity and attach the lead to the heart wall. In 1975 theintroduction of the lithium-iodide battery prolonged the battery life ofa pacemaker from a few months to more than a decade. The modernpacemaker can treat a variety of different signaling pathologies in thecardiac muscle, and can serve as a defibrillator as well (see U.S. Pat.No. 6,738,667 to DENO, et al., the disclosure of which is incorporatedherein by reference). Because the leads are implanted within thepatient, the pacemaker is an example of an implantable medical device.

Another such example is electrical stimulation of the brain withimplanted electrodes (deep brain stimulation), which has been approvedfor use in the treatment of various conditions, including pain andmovement disorders such as essential tremor and Parkinson's disease[Joel S. PERLMUTTER and Jonathan W. Mink. Deep brain stimulation. Annu.Rev. Neurosci 29 (2006):229-257].

Another application of electrical stimulation of nerves is the treatmentof radiating pain in the lower extremities by stimulating the sacralnerve roots at the bottom of the spinal cord [Paul F. WHITE, shitong Liand Jen W. Chiu. Electroanalgesia: Its Role in Acute and Chronic PainManagement. Anesth Analg 92 (2001):505-513; U.S. Pat. No. 6,871,099,entitled Fully implantable microstimulator for spinal cord stimulationas a therapy for chronic pain, to WHITEHURST, et al].

The form of electrical stimulation that is most relevant to the presentinvention is vagus nerve stimulation (VNS, also known as vagal nervestimulation). It was developed initially for the treatment of partialonset epilepsy and was subsequently developed for the treatment ofdepression and other disorders. The left vagus nerve is ordinarilystimulated at a location within the neck by first surgically implantingan electrode there and then connecting the electrode to an electricalstimulator [U.S. Pat. No. 4,702,254 entitled Neurocybernetic prosthesis,to ZABARA; U.S. Pat. No. 6,341,236 entitled Vagal nerve stimulationtechniques for treatment of epileptic seizures, to OSORIO et al; U.S.Pat. No. 5,299,569 entitled Treatment of neuropsychiatric disorders bynerve stimulation, to WERNICKE et al; G. C. ALBERT, C. M. Cook, F. S.Prato, A. W. Thomas. Deep brain stimulation, vagal nerve stimulation andtranscranial stimulation: An overview of stimulation parameters andneurotransmitter release. Neuroscience and Biobehavioral Reviews 33(2009):1042-1060; GROVES D A, Brown V J. Vagal nerve stimulation: areview of its applications and potential mechanisms that mediate itsclinical effects. Neurosci Biobehav Rev 29 (2005):493-500; Reese TERRY,Jr. Vagus nerve stimulation: a proven therapy for treatment of epilepsystrives to improve efficacy and expand applications. Conf Proc IEEE EngMed Biol Soc. 2009; 2009:4631-4634; Timothy B. MAPSTONE. Vagus nervestimulation: current concepts. Neurosurg Focus 25 (3, 2008):E9, pp. 1-4;ANDREWS, R. J. Neuromodulation. I. Techniques-deep brain stimulation,vagus nerve stimulation, and transcranial magnetic stimulation. Ann.N.Y. Acad. Sci. 993 (2003):1-13; LABINER, D. M., Ahern, G. L. Vagusnerve stimulation therapy in depression and epilepsy: therapeuticparameter settings. Acta. Neurol. Scand. 115 (2007):23-33; AMAR, A. P.,Levy, M. L., Liu, C. Y., Apuzzo, M. L. J. Vagus nerve stimulation.Proceedings of the IEEE 96(7, 2008)1142-1151].

Many such therapeutic applications of electrical stimulation involve thesurgical implantation of electrodes within a patient. In contrast,devices used for the procedures that are disclosed here do not involvesurgery, i.e., they are not implantable medical devices. Instead, thepresent devices and methods stimulate nerves by transmitting energy tonerves and tissue non-invasively. A medical procedure is defined asbeing non-invasive when no break in the skin (or other surface of thebody, such as a wound bed) is created through use of the method, andwhen there is no contact with an internal body cavity beyond a bodyorifice (e.g., beyond the mouth or beyond the external auditory meatusof the ear). Such non-invasive procedures are distinguished frominvasive procedures (including minimally invasive procedures) in thatthe invasive procedures insert a substance or device into or through theskin (or other surface of the body, such as a wound bed) or into aninternal body cavity beyond a body orifice.

For example, transcutaneous electrical stimulation of a nerve isnon-invasive because it involves attaching electrodes to the skin, orotherwise stimulating at or beyond the surface of the skin or using aform-fitting conductive garment, without breaking the skin [ThierryKELLER and Andreas Kuhn. Electrodes for transcutaneous (surface)electrical stimulation. Journal of Automatic Control, University ofBelgrade 18(2, 2008):35-45; Mark R. PRAUSNITZ. The effects of electriccurrent applied to skin: A review for transdermal drug delivery.Advanced Drug Delivery Reviews 18 (1996) 395-425]. In contrast,percutaneous electrical stimulation of a nerve is minimally invasivebecause it involves the introduction of an electrode under the skin, vianeedle-puncture of the skin.

Another form of non-invasive electrical stimulation is magneticstimulation. It involves the induction, by a time-varying magneticfield, of electrical fields and current within tissue, in accordancewith Faraday's law of induction. Magnetic stimulation is non-invasivebecause the magnetic field is produced by passing a time-varying currentthrough a coil positioned outside the body. An electric field is inducedat a distance, causing electric current to flow within electricallyconducting bodily tissue. The electrical circuits for magneticstimulators are generally complex and expensive and use a high currentimpulse generator that may produce discharge currents of 5,000 amps ormore, which is passed through the stimulator coil to produce a magneticpulse. The principles of electrical nerve stimulation using a magneticstimulator, along with descriptions of medical applications of magneticstimulation, are reviewed in: Chris HOVEY and Reza Jalinous, The Guideto Magnetic Stimulation, The Magstim Company Ltd, Spring Gardens,Whitland, Carmarthenshire, SA34 0HR, United Kingdom, 2006. In contrast,the magnetic stimulators that have been disclosed by the presentApplicant are relatively simpler devices that use considerably smallercurrents within the stimulator coils. Accordingly, they are intended tosatisfy the need for simple-to-use and less expensive non-invasivemagnetic stimulation devices.

Potential advantages of such non-invasive medical methods and devicesrelative to comparable invasive procedures are as follows. The patientmay be more psychologically prepared to experience a procedure that isnon-invasive and may therefore be more cooperative, resulting in abetter outcome. Non-invasive procedures may avoid damage of biologicaltissues, such as that due to bleeding, infection, skin or internal organinjury, blood vessel injury, and vein or lung blood clotting.Non-invasive procedures are generally painless and may be performedwithout the dangers and costs of surgery. They are ordinarily performedeven without the need for local anesthesia. Less training may berequired for use of non-invasive procedures by medical professionals. Inview of the reduced risk ordinarily associated with non-invasiveprocedures, some such procedures may be suitable for use by the patientor family members at home or by first-responders at home or at aworkplace. Furthermore, the cost of non-invasive procedures may besignificantly reduced relative to comparable invasive procedures.

In co-pending, commonly assigned patent applications, Applicantdisclosed noninvasive electrical and magnetic vagus nerve stimulationdevices, which are adapted, and for certain applications improved, inthe present disclosure [application Ser. No. 13/183,765 and PublicationUS2011/0276112, entitled Devices and methods for non-invasive capacitiveelectrical stimulation and their use for vagus nerve stimulation on theneck of a patient, to SIMON et al.; application Ser. No. 12/964,050 andPublication US2011/0125203, entitled Magnetic Stimulation Devices andMethods of Therapy, to SIMON et al.; and other co-pending commonlyassigned applications that are cited herein, which are incorporated byreference]. The present disclosure elaborates on the electricalstimulation device, rather than the magnetic stimulation device that hassimilar functionality, with the understanding that unless it isotherwise indicated, the elaboration could apply to either theelectrical or the magnetic nerve stimulation device.

The non-invasive nerve stimulator may be applied to the patient by atrained healthcare provider or by the patient himself or herself, afterhaving been evaluated and trained in its use by the healthcare provider.The primary advantage of the self-stimulation therapy is that it can beadministered more or less immediately when symptoms occur, rather thanhaving to visit the healthcare provider at a clinic or emergency room.The need for such a visit would only compound the aggravation that thepatient is already experiencing. Another advantage of theself-stimulation therapy is the convenience of providing the therapy inthe patient's home or workplace, which eliminates schedulingdifficulties, for example, when the nerve stimulation is beingadministered for prophylactic reasons at odd hours of the day.Furthermore, the cost of the treatment may be reduced by not requiringthe involvement of a trained healthcare provider.

However, a disadvantage of having patients apply the therapy tothemselves is that the patient may not always perform the therapy in anoptimal fashion, despite having been trained by the caregiver to do so.Furthermore, individual patients may vary in their responsiveness to thetherapy, even if it is performed in an optimal fashion. Even the samepatient may exhibit day-to-day variations in responsiveness to thetherapy. Accordingly, there is need in the art for devices and methodsthat aid the caregiver and the patient in assuring that the therapy isbeing administered in an optimal fashion, such that the therapy will bemaximally effective and yet have minimum undesirable side-effects. Inparticular, there is a need for methods to assure that the stimulationis always being performed at an optimal anatomical location on thepatient, that the therapy is unambiguously stimulating the target nerve(e.g., vagus nerve), and that the level of stimulation istherapeutically appropriate, as explained in more detail below.

Electrical stimulation by the disclosed methods and devices may be usedto treat many medical conditions, including the conditions that aredescribed in the cited co-pending, commonly assigned patentapplications. An exemplary teaching of the present invention is thetreatment of migraine and other primary headaches such as clusterheadaches, including sinus symptoms (“sinus” headaches) irrespective ofwhether those symptoms arise from an allergy that is co-morbid with theheadache. Background information concerning the treatment of migraineheadaches by noninvasive vagus nerve stimulation will now be summarized.For more detailed background information on the use of such stimulationto treat migraine/sinus headaches, please refer to co-pending, commonlyassigned application number U.S. Ser. No. 13/109,250 with publicationnumber US20110230701, entitled Electrical and magnetic stimulators usedto treat migraine/sinus headache and comorbid disorders to SIMON et al;and application number U.S. Ser. No. 13/183,721 with publication numberUS20110276107, entitled Electrical and magnetic stimulators used totreat migraine/sinus headache, rhinitis, sinusitis, rhinosinusitis, andcomorbid disorders, to SIMON et al, which are incorporated by reference.

Chronic daily headache by definition occurs with a frequency of at least15 headache days per month for greater than 3 months duration. Chronicmigraine sufferers comprise a subset of the population of chronicheadache sufferers, as do those who suffer other primary headachedisorders such as chronic tension-type headache [Bert B. VARGAS, DavidW. Dodick. The Face of Chronic Migraine: Epidemiology, Demographics, andTreatment Strategies. Neurol Clin 27 (2009) 467-479; Peter J. GOADSBY,Richard B. Lipton, Michel D. Ferrari. Migraine—Current understanding andtreatment. N Engl J Med 346 (4, 2002): 257-270; Stephen D SILBERSTEIN.Migraine. LANCET 363 (2004):381-391].

A migraine headache typically passes through the following stages:prodromal, aura, headache pain, and postdromal. All these phases do notnecessarily occur, and there is not necessarily a distinct onset or endof each stage, with the possible exception of the aura. An interictalperiod follows the postdromal, unless the postrome of one migraineattack overlaps the prodrome of the next migraine attack.

The prodrome stage comprises triggering events followed by premonitorysymptoms. The prodrome is often characterized by fatigue, sleepiness,elation, food cravings, depression, and irritability, among othersymptoms. Triggers (also called precipitating factors) such as excessivestress or sensory barrage usually precede the attack by less than 48 h.The average duration of the prodrome is 6 to 10 hours, but in half ofmigraine attacks, the prodrome is less than two hours (or absent), andin approximately 15% of migraine attacks, the prodrome lasts for 12hours to 2 days.

The aura is due to cortical spreading depression within the brain.Approximately 20-30% of migraine sufferers experience an aura,ordinarily a visual aura, which is perceived by the patient as ascintillating scotoma (zig-zag line) that moves within the patient'svisual field for typically half an hour. However, aura symptoms,regardless of their form, vary to a great extent in duration andseverity from patient to patient, and also within the same individual.

Although the headache phase can begin at any hour, it most commonlybegins as mild pain when the patient awakens in the morning. It thengradually builds at variable rates to reach a peak at which the pain isusually described as moderate to severe. Migraine headaches often occuron both sides of the head in children, but an adult pattern ofunilateral pain often emerges in adolescence. The pain is often reportedas starting in the occipital/neck regions, later becomingfrontotemporal. It is throbbing and aggravated by physical effort, withall stimuli tending to accentuate the headache. The pain phase lasts4-72 h in adults and 1-72 h in children, with a mean duration generallyof less than 1 day. The pain intensity usually follows a smooth curvewith a crescendo with a diminuendo. After the headache has resolved,many patients are left with a postdrome that lingers for one to twodays. The main complaints during the prodrome are cognitivedifficulties, such as mental tiredness.

For the present medical applications, an electrical stimulator device isordinarily applied to the patient's neck. In a preferred embodiment ofthe invention, the stimulator comprises two electrodes that lieside-by-side within separate stimulator heads, wherein the electrodesare separated by electrically insulating material. Each electrode andthe patient's skin are connected electrically through an electricallyconducting medium that extends from the skin to the electrode. The levelof stimulation power may be adjusted with a wheel or other controlfeature that also serves as an on/off switch.

The position and angular orientation of the device are adjusted about alocation on the neck until the patient perceives stimulation whencurrent is passed through the stimulator electrodes. An objective of thepresent invention is to assure that the position of the stimulator onthe neck is therapeutically optimal. The following related issue alsoarises. Although the stimulator is designed to be robust against verysmall variations in position of the stimulator relative to the vagusnerve, fluctuating movement of the stimulator relative to the nervebeing stimulated is to some extent unavoidable, due for example to neckmuscle contractions that accompany breathing. Such unavoidable movementof the device makes it difficult to assure that the patient is receivingexactly the prescribed stimulation dose in each stimulation session.Accordingly, an objective of the invention is to measure such movementand compensate for it.

The applied current is then increased gradually, first to a levelwherein the patient feels sensation from the stimulation. The power isthen further increased, but is set to a level that is less than one atwhich the patient first indicates any discomfort. Another objective ofthe present invention is to assure that the target nerve (e.g. vagusnerve) is being stimulated, such that the sensation that the patientexperiences is not simply due to electrical current passing through theskin and muscle beneath the stimulator heads.

The electrical stimulation is then typically applied for 5 to 30minutes, which is often sufficient to at least partially relieveheadache pain within 5 minutes. The treatment then causes patients toexperience a very rapid relief from headache pain, as well as a rapidopening of the nasal passages within approximately 20 minutes. Effectsof the treatment may last for 4 to 5 hours or longer. However, for somepatients the stimulation is performed for prophylactic purposes, i.e.,to prevent a headache from occurring, such that the patient cannot useprompt relief of headache pain as an indication of whether thestimulation was being performed optimally. Furthermore, when the patientis being instructed in the use of the stimulator by a caregiver, suchinstruction may take place when no headache is in progress. Accordingly,another objective of the present invention is to assure that thestimulation parameters are being set in an optimal fashion during atherapeutic session, without necessarily relying on the prompt relief ofsymptoms as a guide for whether the parameter selection was appropriate(e.g., selection of stimulation amplitude).

Despite the advantages of having a patient administer the nervestimulation by himself or herself, such self-stimulation also presentscertain risks and difficulties relating to safety. In some situations,the vagus nerve stimulator should be applied to the left or to the rightvagus nerve, but not vice versa. In some situations, it would bebeneficial to apply the stimulator to both sides of the neck in aprescribed order. On the other hand, in some situations the stimulationmay actually be most beneficial if applied to the right vagus nerve, andit may be relatively less effective if applied to the left vagus nerve.Therefore, if the patient is using the vagus nerve stimulator by himselfor herself, it would be useful for the device be designed so that it canbe used only on the prescribed side of the neck. The present inventiondiscloses several methods for preventing inadvertent stimulation on theside of the neck that is not prescribed.

Another problem is that the patient may wish to stop the stimulationsession based only on some subjective assessment of whether thestimulation has sufficiently relieved the symptoms. However, there maybe a diminishing effectiveness if the stimulation session is too long,for the following reason. Let the numerical value of the accumulatedeffects of vagus nerve stimulation be denoted as S(t). It may forpresent exemplary purposes be represented as a function that increasesat a rate proportional to the stimulation voltage V in the vicinity ofthe nerve and decays with a time constant τ_(P), such that afterprolonged stimulation, the accumulated stimulation effectiveness maysaturate at a value equal to the product of V and τ_(p). Thus, if T_(p)is the duration of a vagus nerve stimulation in a particular treatmentsession, then for time t<T_(p), S(t)=Vτ[1−exp(−t/τ_(p))]+S₀exp(−t/τ_(p)), and for t>T_(p), S(t)=S(T_(p))exp(−[t−T_(p)]/τ_(p)),where the time t is measured from the start of a stimulus, and S₀ is thevalue of S when t=0. The optimal duration of a stimulation session maybe different from patient to patient, because the decay time constanttip may vary from patient to patient. To the extent that the stimulationprotocol is designed to treat each patient individually, such thatsubsequent treatment sessions are designed in view of the effectivenessof previous treatment sessions, it is would be useful for thestimulation amplitude V be as constant as possible, and the treatmentsession should take into account the above-mentioned principle ofdiminishing returns. At a minimum, the average stimulation amplitude ina session should be estimated or evaluated, despite movement of thestimulator relative to the nerve and despite any amplitude adjustment bythe patient. The present invention discloses methods and devices fordoing so.

SUMMARY OF THE INVENTION

Devices are disclosed that are used to treat a medical condition, suchas migraine headache, by electrically stimulating a nerve noninvasively,wherein electrodes are placed against the skin of the patient. Inpreferred embodiments of the invention, the nerve is a vagus nerve thatlies under the skin of the patient's neck. Preferred embodiments of thedevices and methods allow a patient to self-treat his or her condition,after having been trained by a caregiver. Methods are disclosed thatassure that the device is positioned optimally on the neck and that theamplitude and other stimulation parameters result in therapeuticstimulation of a vagus nerve.

The system comprises a dual-electrode stimulator housing that is appliedto the surface of the patient's neck, and it may also include a dockingstation that is used to charge a rechargeable battery within thestimulator housing. The docking station and stimulator housing alsotransmit data to one another regarding the status of a stimulationsession, prior to and after the session and possibly also during thesession. They also transmit data to and from a computer program in apatient interface device, such as a mobile phone or nearby computer.Such data transmission to and from the patient interface device ispreferably wireless, but wired communication between devices is alsocontemplated. The interface device, and possibly the stimulator ordocking station, in turn communicates with other computers containingmedical record and billing databases, via the internet. Methods aredescribed wherein medical records are used and updated during the courseof a stimulation session, and wherein payment for a treatment session ismade.

The system is designed to address problems that may arise duringself-treatment, when a medical professional is not present. The mostsignificant problem is to assure that the patient is in fact stimulatinga vagus nerve. Failure to do so may be because the stimulator ispositioned incorrectly on the neck, or because the amplitude or otherstimulation parameters are inappropriate. Other potential problems thatthe invention addresses are that the patient may attempt to stimulate avagus nerve on the wrong side of the neck (left or right), minimizing ordocumenting motion of the stimulator, documenting the patient'sadjustment of the stimulation amplitude, and controlling the amount ofenergy that can be delivered to the patient during a stimulationsession.

The optimal stimulation position on the neck is initially determined bya caregiver, using ultrasound imaging of the vagus nerve and othercriteria. That position is “tattoo”-marked on the patient's skin, usingfluorescent dyes that are essentially invisible unless illuminated withultraviolet or infrared light. When the patient later performsself-stimulation using the device, the device uses internal opticalinstrumentation to determine that the device is aligned with the“tattoo”-marks.

The parameters for the protocol of each stimulation session aretransmitted via the docking station to the stimulator device from aphysician-controlled computer, which provides authorization for thecharging of the stimulator device's batteries by the docking station.Parameters of the stimulation protocol may be varied in response toheterogeneity in the symptoms of patients. Different stimulationparameters may also be selected as the course of the patient's medicalcondition changes. In preferred embodiments, the disclosed stimulationmethods and devices do not produce clinically significant side effects,such as agitation or anxiety, or changes in heart rate or bloodpressure.

In a preferred embodiment of the invention, the stimulator housingcomprises a rechargeable source of electrical power and two or moreremote electrodes that are configured to stimulate a deep nerve. Thestimulator may comprise two electrodes that lie side-by-side within ahand-held housing, wherein the electrodes are separated by electricallyinsulating material. Each electrode is in continuous contact with anelectrically conducting medium that extends from the patient-interfaceelement of the stimulator to the electrode. The interface elementcontacts the patient's skin when the device is in operation.

Current passing through an electrode may be about 0 to 40 mA, withvoltage across the electrodes of about 0 to 30 volts. The current ispassed through the electrodes in bursts of pulses. There may be 1 to 20pulses per burst, preferably five pulses. Each pulse within a burst hasa duration of about 20 to 1000 microseconds, preferably 200microseconds. A burst followed by a silent inter-burst interval repeatsat 1 to 5000 bursts per second (bps, similar to Hz), preferably at 15-50bps, and even more preferably at 25 bps. The preferred shape of eachpulse is a full sinusoidal wave.

A source of power supplies a pulse of electric charge to the electrodes,such that the electrodes produce an electric current and/or an electricfield within the patient. The electrical stimulator is configured toinduce a peak pulse voltage sufficient to produce an electric field inthe vicinity of a nerve such as a vagus nerve, to cause the nerve todepolarize and reach a threshold for action potential propagation. Byway of example, the threshold electric field for stimulation of thenerve may be about 8 V/m at 1000 Hz. For example, the device may producean electric field within the patient of about 10 to 600 V/m (preferablyless than 100 V/m) and an electrical field gradient of greater than 2V/m/mm. Electric fields that are produced at the vagus nerve aregenerally sufficient to excite all myelinated A and B fibers, but notnecessarily the unmyelinated C fibers. However, by using a reducedamplitude of stimulation, excitation of A-delta and B fibers may also beavoided.

The preferred stimulator shapes an elongated electric field of effectthat can be oriented parallel to a long nerve, such as a vagus. Byselecting a suitable waveform to stimulate the nerve, along withsuitable parameters such as current, voltage, pulse width, pulses perburst, inter-burst interval, etc., the stimulator produces acorrespondingly selective physiological response in an individualpatient. Such a suitable waveform and parameters are simultaneouslyselected to avoid substantially stimulating nerves and tissue other thanthe target nerve, particularly avoiding the stimulation of nerves in theskin that produce pain.

Demonstration that a vagus nerve is in fact being stimulated isinitially undertaken by the caregiver, who marks the optimal stimulationsite on the patient's skin with a fluorescent dye. Verification that thevagus nerve is being stimulated is also undertaken later by the patientduring self-treatment. Methods used by the caregiver to verifystimulation may make use of ultrasound, radiological imaging, autonomictesting and other equipment that is not available to the patient athome. However, other methods for verifying vagus nerve stimulation, suchas analysis of the patient's speech or monitoring the diameter of apupil of the patient's eye, may be implemented for home use, forexample, in a mobile phone app.

The following methods for verifying and monitoring stimulation of thevagus nerve rely on the stimulated vagus nerve causing somephysiological response that can be measured, such as some change in thepatient's voice (by virtue of stimulation of a recurrent laryngealnerve, which is a branch of the vagus nerve), autonomic nervous system,evoked potential, chemistry of the blood, or blood flow within thebrain.

One method for demonstrating stimulation of a vagus nerve is to measurean increased vagal artery blood flow, preferably using ultrasoundcontrast agents.

A method involving laryngeal electromography is as follows. Surfaceelectrode arrays are placed symmetrically on both sides of the larynx.Before the vagus nerve is stimulated electrically, but when speech isuttered by the patient, correspondence is made between particular arrayelements in the left and right arrays, based on the similarity of theirsignals. Then, as vagus stimulation is applied and its amplitude isincreased, the signals from corresponding array elements in the twoarrays become increasingly asymmetric during speech or other laryngealactivity, by virtue of the fact that the vagus nerve stimulationpreferentially modulates the activity of laryngeal muscles only on oneside of the neck.

Acoustic methods for demonstrating vagus nerve stimulation are based onan analysis of the patient's speech, as follows. The patient performs amonotonous pitch raise (continuous glissando), in which he or shephonates a vowel such as /a/ from a low pitch up to a much higher one,spanning multiple voice registers. The speech is transduced by amicrophone and is digitized at about 20 to 40 kHz at 16 bits. Theresulting time-series is broken into many time segments; and classicaland nonlinear acoustic indices are calculated for each of them (e.g.,fundamental frequency, jitter, shimmer, relative power in the first fiveindividual harmonic frequencies, Lyapunov exponent).

This set of acoustic data may be supplemented with simultaneouslyacquired electroglottographic data and/or indices of laryngealelectromyographic asymmetry. Such data with and without vagus nervestimulation are presented to a support vector machine which, aftertraining, is able to predict from test acoustic data (and/orelectroglottographic data and/or electromyographic asymmetry data)whether or not the vagus nerve is being stimulated. One feature that thesupport vector machine is likely to use in making the classification isas follows. As the patient raises his or her pitch slowly, the larynxshifts from one vocal mode to another at particular frequencies,analogous to an automobile shifting gears. According to the presentinvention, the frequencies at which those transitions occur may change,depending on the amplitude of vagus nerve stimulation.

The present invention may also make use of autonomic nervous systemmeasurements, which may be used individually or as part of a set of datathat is provided to a support vector machine for deciding whether thevagus nerve is being stimulated. The autonomic indices that arepreferably measured involve electrodermal activity, heart ratevariability, and responses related to the control of pupil diameter andblood flow to the eye, as a function of the amplitude of vagus nervestimulation.

Additional measurements may be made to assess the existence of effectsof vagus nerve stimulation on the autonomic nervous system, comparingdata before, during and after the nerve stimulation. They includeperipheral blood flow measured with laser Doppler flow meters,simultaneous heart rate and blood pressure variability analysis,valsalva maneuver, deep metronomic breathing, a sustained handgrip test,a cold pressor test, a cold face test, active and passive orthostaticchallenge maneuvers, blood pressure response to a mental arithmetictest, pharmacological baroreflex testing, a thermoregulatory sweat test,and a quantitative sudomotor axon reflex test.

Imaging of cerebral blood flow may also be performed to demonstrate theexistence of effects of vagus nerve stimulation, comparing the locationand magnitude of blood flow before, during and after the nervestimulation. The imaging may comprise positron emission tomography,functional magnetic resonance imaging (fMRI), and single-photon emissioncomputed tomography (SPECT).

Additional tests for whether the vagus nerve is being stimulated mayinvolve evaluation of electroencephalography (EEG) waveforms and/or themeasurement of visual, audio and somatosensory evoked potentials.Changes in absolute vital sign values may also be used to demonstratethat the vagus nerve has been stimulated (absolute heart rate,respiration rate, blood pressure), although if such changes areobserved, it might also be concluded that the parameters of thestimulation may best be changed so as not to stimulate vagal C fibers.

Other tests for whether the vagus nerve is being stimulated includechanges in pain threshold, changes in balance or sway, and changes inthe chemistry of blood or other bodily fluids, as a function of theamplitude of vagus nerve stimulation. The blood chemistry tests involvethe measurement of such chemicals as TNF-alpha, other cytokines,serotonin, gastrin, and/or norepinephrine.

Treating a medical condition such as migraine headache may beimplemented within the context of control theory. A controllercomprising, for example, the disclosed nerve stimulator, a PID, and afeedback or feedforward model, provides input to the patient viastimulation of one or both of the patient's vagus nerves. The signalsused to control the stimulation comprise physiological or environmentalvariables that are measured with sensors. In one embodiment, the vagusnerve stimulation is varied as a function of motion of the stimulator,which is measured using accelerometers.

The novel systems, devices and methods for treating medical conditionsuch as migraine headache are more completely described in the followingdetailed description of the invention, with reference to the drawingsprovided herewith, and in claims appended hereto. Other aspects,features, advantages, etc. will become apparent to one skilled in theart when the description of the invention herein is taken in conjunctionwith the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

For the purposes of illustrating the various aspects of the invention,there are shown in the drawings forms that are presently preferred, itbeing understood, however, that the invention is not limited by or tothe precise data, methodologies, arrangements and instrumentalitiesshown, but rather only by the claims.

FIG. 1 is a schematic view of nerve modulating devices according to thepresent invention, which supply controlled pulses of electrical currentto surface electrodes.

FIG. 2A illustrates an exemplary electrical voltage/current profile forstimulating and/or modulating impulses that are applied to a nerveaccording to the present invention;

FIG. 2B illustrates an exemplary electrical waveform for stimulatingand/or modulating impulses that are applied to a nerve according to thepresent invention;

FIG. 2C illustrates a larger portion of the electrical waveform shown inFIG. 2B;

FIG. 3A is a perspective view of a dual-electrode stimulator accordingto an embodiment of the present invention;

FIG. 3B is a perspective view of the other side of the dual-electrodestimulator shown in FIG. 3A;

FIG. 3C illustrates an exemplary docking station for the dual-electrodestimulator of FIG. 3A;

FIG. 3D illustrates a monitoring system for non-invasive vagal nervestimulation according to the present invention;

FIG. 4A illustrates a remote control device for communicating with thedocking station of FIG. 3C;

FIG. 4B illustrates a mobile phone for communicating with the dockingstation of FIG. 3C;

FIG. 4C illustrates a touchscreen device for communicating with thedocking station of FIG. 3C;

FIG. 4D illustrates a laptop computer for communicating with the dockingstation of FIG. 3C;

FIG. 5 shows an expanded diagram of the control unit shown in FIG. 1,separating components of the control unit into those within the body ofthe stimulator, those within the docking station, and those withinhand-held and internet-based devices, also showing communication pathsbetween such components.

FIG. 6A illustrates the approximate position of the housing of thestimulator according to one embodiment of the present invention whenused to stimulate the right vagus nerve in the neck of an adult patient;

FIG. 6B illustrates the positions of an electrode array according to thepresent invention for monitoring vagal nerve stimulation via laryngealelectromyography and electroglottography.

FIG. 7 illustrates the approximate position of the housing of thestimulator in a neck collar according one embodiment of the presentinvention, when used to stimulate the right vagus nerve in the neck of achild.

FIG. 8 illustrates the housing of the stimulator according oneembodiment of the present invention, when positioned to stimulate avagus nerve in the patient's neck, wherein the stimulator is applied tothe surface of the neck in the vicinity of the identified anatomicalstructures.

FIG. 9 illustrates connections between the controller and controlledsystem according to the present invention, their input and outputsignals, and external signals from the environment.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the present invention, electrodes applied to the skin of the patientgenerate currents within the tissue of the patient. An objective of theinvention is to produce and apply the electrical impulses so as tointeract with the signals of one or more nerves, in order to achieve thetherapeutic result. Much of the disclosure will be directed specificallyto treatment of a patient by electromagnetic stimulation in or around avagus nerve, with devices positioned non-invasively on or near apatient's neck. However, it will also be appreciated that the devicesand methods of the present invention can be applied to other tissues andnerves of the body, including but not limited to other parasympatheticnerves, sympathetic nerves, spinal or cranial nerves.

Description of the Nerve Stimulating/Modulating Devices

Devices of the invention that are used to stimulate a vagus nerve willnow be described.

An embodiment of the present invention is shown in FIG. 1, which is aschematic diagram of an electrode-based nerve stimulating/modulatingdevice 302 for delivering impulses of energy to nerves for the treatmentof medical conditions. As shown, device 302 may include an impulsegenerator 310; a power source 320 coupled to the impulse generator 310;a control unit 330 in communication with the impulse generator 310 andcoupled to the power source 320; and electrodes 340 coupled via wires345 to impulse generator 310. In a preferred embodiment, the sameimpulse generator 310, power source 320, and control unit 330 may beused for either a magnetic stimulator or the electrode-based stimulator302, allowing the user to change parameter settings depending on whethermagnetic coils or the electrodes 340 are attached. Although a pair ofelectrodes 340 is shown in FIG. 1, in practice the electrodes may alsocomprise three or more distinct electrode elements, each of which isconnected in series or in parallel to the impulse generator 310. Thus,the electrodes 340 that are shown in FIG. 1 represent all electrodes ofthe device collectively.

The item labeled in FIG. 1 as 350 is a volume, contiguous with anelectrode 340, that is filled with electrically conducting medium. Theconducting medium in which the electrode 340 is embedded need notcompletely surround an electrode. The volume 350 is electricallyconnected to the patient at a target skin surface in order to shape thecurrent density passed through an electrode 340 that is needed toaccomplish stimulation of the patient's nerve or tissue. The electricalconnection to the patient's skin surface is through an interface 351. Inone embodiment, the interface is made of an electrically insulating(dielectric) material, such as a thin sheet of Mylar. In that case,electrical coupling of the stimulator to the patient is capacitive. Inother embodiments, the interface comprises electrically conductingmaterial, such as the electrically conducting medium 350 itself, or anelectrically conducting or permeable membrane. In that case, electricalcoupling of the stimulator to the patient is ohmic. As shown, theinterface may be deformable such that it is form-fitting when applied tothe surface of the body. Thus, the sinuousness or curvature shown at theouter surface of the interface 351 corresponds also to sinuousness orcurvature on the surface of the body, against which the interface 351 isapplied, so as to make the interface and body surface contiguous.

The control unit 330 controls the impulse generator 310 to generate asignal for each of the device's coils or electrodes. The signals areselected to be suitable for amelioration of a particular medicalcondition, when the signals are applied non-invasively to a target nerveor tissue via the electrodes 340. It is noted that nervestimulating/modulating device 302 may be referred to by its function asa pulse generator. Patent application publications US2005/0075701 andUS2005/0075702, both to SHAFER, contain descriptions of pulse generatorsthat may be applicable to the present invention. By way of example, apulse generator is also commercially available, such as Agilent 33522AFunction/Arbitrary Waveform Generator, Agilent Technologies, Inc., 5301Stevens Creek Blvd Santa Clara Calif. 95051.

The control unit 330 may also comprise a general purpose computer,comprising one or more CPU, computer memories for the storage ofexecutable computer programs (including the system's operating system)and the storage and retrieval of data, disk storage devices,communication devices (such as serial and USB ports) for acceptingexternal signals from the system's keyboard, computer mouse, andtouchscreen, as well as any externally supplied physiological signals(see FIG. 9), analog-to-digital converters for digitizing externallysupplied analog signals (see FIG. 9), communication devices for thetransmission and receipt of data to and from external devices such asprinters and modems that comprise part of the system, hardware forgenerating the display of information on monitors that comprise part ofthe system, and busses to interconnect the above-mentioned components.Thus, the user may operate the system by typing instructions for thecontrol unit 330 at a device such as a keyboard and view the results ona device such as the system's computer monitor, or direct the results toa printer, modem, and/or storage disk. Control of the system may bebased upon feedback measured from externally supplied physiological orenvironmental signals. Alternatively, the control unit 330 may have acompact and simple structure, for example, wherein the user may operatethe system using only an on/off switch and power control wheel or knob.In a section below, a preferred embodiment is described wherein thestimulator housing has a simple structure, but other components of thecontrol unit 330 are distributed into other devices (see FIG. 5).

Parameters for the nerve or tissue stimulation include power level,frequency and train duration (or pulse number). The stimulationcharacteristics of each pulse, such as depth of penetration, strengthand selectivity, depend on the rise time and peak electrical energytransferred to the electrodes, as well as the spatial distribution ofthe electric field that is produced by the electrodes. The rise time andpeak energy are governed by the electrical characteristics of thestimulator and electrodes, as well as by the anatomy of the region ofcurrent flow within the patient. In one embodiment of the invention,pulse parameters are set in such as way as to account for the detailedanatomy surrounding the nerve that is being stimulated [Bartosz SAWICKI,Robert Szmuro, Przemyslaw Ponecki, Jacek Starzy ski, StanisawWincenciak, Andrzej Rysz. Mathematical Modelling of Vagus NerveStimulation. pp. 92-97 in: Krawczyk, A. Electromagnetic Field, Healthand Environment: Proceedings of EHE'07. Amsterdam, 105 Press, 2008].Pulses may be monophasic, biphasic or polyphasic. Embodiments of theinvention include those that are fixed frequency, where each pulse in atrain has the same inter-stimulus interval, and those that havemodulated frequency, where the intervals between each pulse in a traincan be varied.

FIG. 2A illustrates an exemplary electrical voltage/current profile fora stimulating, blocking and/or modulating impulse applied to a portionor portions of selected nerves in accordance with an embodiment of thepresent invention. For the preferred embodiment, the voltage and currentrefer to those that are non-invasively produced within the patient bythe stimulator coils or electrodes. As shown, a suitable electricalvoltage/current profile 400 for the blocking and/or modulating impulse410 to the portion or portions of a nerve may be achieved using pulsegenerator 310. In a preferred embodiment, the pulse generator 310 may beimplemented using a power source 320 and a control unit 330 having, forinstance, a processor, a clock, a memory, etc., to produce a pulse train420 to the electrodes 340 that deliver the stimulating, blocking and/ormodulating impulse 410 to the nerve. Nerve stimulating/modulating device302 may be externally powered and/or recharged or may have its own powersource 320. The parameters of the modulation signal 400, such as thefrequency, amplitude, duty cycle, pulse width, pulse shape, etc., arepreferably programmable. An external communication device may modify thepulse generator programming to improve treatment.

In addition, or as an alternative to the devices to implement themodulation unit for producing the electrical voltage/current profile ofthe stimulating, blocking and/or modulating impulse to the electrodes,the device disclosed in patent publication No. US2005/0216062 may beemployed. That patent publication discloses a multifunctional electricalstimulation (ES) system adapted to yield output signals for effectingelectromagnetic or other forms of electrical stimulation for a broadspectrum of different biological and biomedical applications, whichproduce an electric field pulse in order to non-invasively stimulatenerves. The system includes an ES signal stage having a selector coupledto a plurality of different signal generators, each producing a signalhaving a distinct shape, such as a sine wave, a square or a saw-toothwave, or simple or complex pulse, the parameters of which are adjustablein regard to amplitude, duration, repetition rate and other variables.Examples of the signals that may be generated by such a system aredescribed in a publication by LIBOFF [A. R. LIBOFF. Signal shapes inelectromagnetic therapies: a primer. pp. 17-37 in: BioelectromagneticMedicine (Paul J. Rosch and Marko S. Markov, eds.). New York: MarcelDekker (2004)]. The signal from the selected generator in the ES stageis fed to at least one output stage where it is processed to produce ahigh or low voltage or current output of a desired polarity whereby theoutput stage is capable of yielding an electrical stimulation signalappropriate for its intended application. Also included in the system isa measuring stage which measures and displays the electrical stimulationsignal operating on the substance being treated, as well as the outputsof various sensors which sense prevailing conditions prevailing in thissubstance, whereby the user of the system can manually adjust thesignal, or have it automatically adjusted by feedback, to provide anelectrical stimulation signal of whatever type the user wishes, who canthen observe the effect of this signal on a substance being treated.

The stimulating and/or modulating impulse signal 410 preferably has afrequency, an amplitude, a duty cycle, a pulse width, a pulse shape,etc. selected to influence the therapeutic result, namely, stimulatingand/or modulating some or all of the transmission of the selected nerve.For example, the frequency may be about 1 Hz or greater, such as betweenabout 15 Hz to 100 Hz, more preferably around 25 Hz. The modulationsignal may have a pulse width selected to influence the therapeuticresult, such as about 1 microseconds to about 1000 microseconds. Forexample, the electric field induced or produced by the device withintissue in the vicinity of a nerve may be about 5 to 600 V/m, preferablyless than 100 V/m, and even more preferably less than 30 V/m. Thegradient of the electric field may be greater than 2 V/m/mm. Moregenerally, the stimulation device produces an electric field in thevicinity of the nerve that is sufficient to cause the nerve todepolarize and reach a threshold for action potential propagation, whichis approximately 8 V/m at 1000 Hz. The modulation signal may have a peakvoltage amplitude selected to influence the therapeutic result, such asabout 0.2 volts or greater, such as about 0.2 volts to about 40 volts.

An objective of the disclosed stimulators is to provide both nerve fiberselectivity and spatial selectivity. Spatial selectivity may be achievedin part through the design of the electrode configuration, and nervefiber selectivity may be achieved in part through the design of thestimulus waveform, but designs for the two types of selectivity areintertwined. This is because, for example, a waveform may selectivelystimulate only one of two nerves whether they lie close to one anotheror not, obviating the need to focus the stimulating signal onto only oneof the nerves [GRILL W and Mortimer J T. Stimulus waveforms forselective neural stimulation. IEEE Eng. Med. Biol. 14 (1995): 375-385].These methods complement others that are used to achieve selective nervestimulation, such as the use of local anesthetic, application ofpressure, inducement of ischemia, cooling, use of ultrasound, gradedincreases in stimulus intensity, exploiting the absolute refractoryperiod of axons, and the application of stimulus blocks [John E. SWETTand Charles M. Bourassa. Electrical stimulation of peripheral nerve. In:Electrical Stimulation Research Techniques, Michael M. Patterson andRaymond P. Kesner, eds. Academic Press. (New York, 1981) pp. 243-295].

To date, the selection of stimulation waveform parameters for nervestimulation has been highly empirical, in which the parameters arevaried about some initially successful set of parameters, in an effortto find an improved set of parameters for each patient. A more efficientapproach to selecting stimulation parameters might be to select astimulation waveform that mimics electrical activity in the anatomicalregions that one is attempting stimulate indirectly, in an effort toentrain the naturally occurring electrical waveform, as suggested inpatent number U.S. Pat. No. 6,234,953, entitled Electrotherapy deviceusing low frequency magnetic pulses, to THOMAS et al. and applicationnumber US20090299435, entitled Systems and methods for enhancing oraffecting neural stimulation efficiency and/or efficacy, to GLINER etal. One may also vary stimulation parameters iteratively, in search ofan optimal setting [U.S. Pat. No. 7,869,885, entitled Thresholdoptimization for tissue stimulation therapy, to BEGNAUD et al]. However,some stimulation waveforms, such as those described herein, arediscovered by trial and error, and then deliberately improved upon.

Invasive nerve stimulation typically uses square wave pulse signals.However, Applicant found that square waveforms are not ideal fornon-invasive stimulation as they may produce excessive pain. Prepulsesand similar waveform modifications have been suggested as methods toimprove selectivity of nerve stimulation waveforms, but Applicant didnot find them ideal [Aleksandra VUCKOVIC, Marco Tosato and Johannes J.Struijk. A comparative study of three techniques for diameter selectivefiber activation in the vagal nerve: anodal block, depolarizingprepulses and slowly rising pulses. J. Neural Eng. 5 (2008): 275-286;Aleksandra VUCKOVIC, Nico J. M. Rijkhoff, and Johannes J. Struijk.Different Pulse Shapes to Obtain Small Fiber Selective Activation byAnodal Blocking-A Simulation Study. IEEE Transactions on BiomedicalEngineering 51(5, 2004):698-706; Kristian HENNINGS. Selective ElectricalStimulation of Peripheral Nerve Fibers: Accommodation Based Methods.Ph.D. Thesis, Center for Sensory-Motor Interaction, Aalborg University,Aalborg, Denmark, 2004].

Applicant also found that stimulation waveforms consisting of bursts ofsquare pulses are not ideal for non-invasive stimulation [M. I. JOHNSON,C. H. Ashton, D. R. Bousfield and J. W. Thompson. Analgesic effects ofdifferent pulse patterns of transcutaneous electrical nerve stimulationon cold-induced pain in normal subjects. Journal of PsychosomaticResearch 35 (2/3, 1991):313-321; U.S. Pat. No. 7,734,340, entitledStimulation design for neuromodulation, to De Ridder]. However, burstsof sinusoidal pulses are a preferred stimulation waveform, as shown inFIGS. 2B and 2C. As seen there, individual sinusoidal pulses have aperiod of τ, and a burst consists of N such pulses. This is followed bya period with no signal (the inter-burst period). The pattern of a burstfollowed by silent inter-burst period repeats itself with a period of T.For example, the sinusoidal period τ may be 200 microseconds; the numberof pulses per burst may be N=5; and the whole pattern of burst followedby silent inter-burst period may have a period of T=40000 microseconds,which is comparable to 25 Hz stimulation (a much smaller value of T isshown in FIG. 2C to make the bursts discernable).

When these exemplary values are used for T and τ, the waveform containssignificant Fourier components at higher frequencies ( 1/200microseconds=5000/sec), as compared with those contained intranscutaneous nerve stimulation waveforms, as currently practiced.

Applicant is unaware of such a waveform having been used with vagusnerve stimulation, but a similar waveform has been used to stimulatemuscle as a means of increasing muscle strength in elite athletes.However, for the muscle strengthening application, the currents used(200 mA) may be very painful and two orders of magnitude larger thanwhat are disclosed herein. Furthermore, the signal used for musclestrengthening may be other than sinusoidal (e.g., triangular), and theparameters τ, N, and T may also be dissimilar from the valuesexemplified above [A. DELITTO, M. Brown, M. J. Strube, S. J. Rose, andR. C. Lehman. Electrical stimulation of the quadriceps femoris in anelite weight lifter: a single subject experiment. Int J Sports Med 10(1989):187-191; Alex R WARD, Nataliya Shkuratova. Russian ElectricalStimulation The Early Experiments. Physical Therapy 82 (10, 2002):1019-1030; Yocheved LAUFER and Michal Elboim. Effect of Burst Frequencyand Duration of Kilohertz-Frequency Alternating Currents and ofLow-Frequency Pulsed Currents on Strength of Contraction, MuscleFatigue, and Perceived Discomfort. Physical Therapy 88 (10,2008):1167-1176; Alex R WARD. Electrical Stimulation UsingKilohertz-Frequency Alternating Current. Physical Therapy 89 (2,2009):181-190; J. PETROFSKY, M. Laymon, M. Prowse, S. Gunda, and J.Batt. The transfer of current through skin and muscle during electricalstimulation with sine, square, Russian and interferential waveforms.Journal of Medical Engineering and Technology 33 (2, 2009): 170-181;U.S. Pat. No. 4,177,819, entitled Muscle stimulating apparatus, toKOFSKY et al]. Burst stimulation has also been disclosed in connectionwith implantable pulse generators, but wherein the bursting ischaracteristic of the neuronal firing pattern itself [U.S. Pat. No.7,734,340 to DE RIDDER, entitled Stimulation design for neuromodulation;application US20110184486 to DE RIDDER, entitled Combination of tonicand burst stimulations to treat neurological disorders]. By way ofexample, the electric field shown in FIGS. 2B and 2C may have an E_(max)value of 17 V/m, which is sufficient to stimulate the nerve but issignificantly lower than the threshold needed to stimulate surroundingmuscle.

High frequency electrical stimulation is also known in the treatment ofback pain at the spine [Patent application US20120197369, entitledSelective high frequency spinal cord modulation for inhibiting pain withreduced side effects and associated systems and methods, to ALATARIS etal.; Adrian A L KAISY, Iris Smet, and Jean-Pierre Van Buyten. Analgeiaof axial low back pain with novel spinal neuromodulation. Posterpresentation #202 at the 2011 meeting of The American Academy of PainMedicine, held in National Harbor, Md., Mar. 24-27, 2011]. Those methodsinvolve high-frequency modulation in the range of from about 1.5 KHz toabout 50 KHz, which is applied to the patient's spinal cord region.However, such methods are different from the present invention because,for example, they is invasive; they do not involve a bursting waveform,as in the present invention; they necessarily involve A-delta and Cnerve fibers and the pain that those fibers produce, whereas the presentinvention does not; they may involve a conduction block applied at thedorsal root level, whereas the present invention may stimulate actionpotentials without blocking of such action potentials; and/or theyinvolve an increased ability of high frequency modulation to penetratethrough the cerebral spinal fluid, which is not relevant to the presentinvention. In fact, a likely explanation for the reduced back pain thatis produced by their use of frequencies from 10 to 50 KHz is that theapplied electrical stimulus at those frequencies causes permanent damageto the pain-causing nerves, whereas the present invention involves onlyreversible effects [LEE R C, Zhang D, Hannig J. Biophysical injurymechanisms in electrical shock trauma. Annu Rev Biomed Eng 2(2000):477-509].

Consider now which nerve fibers may be stimulated by the non-invasivevagus nerve stimulation. The vagus nerve (tenth cranial nerve, pairedleft and right) is composed of motor and sensory fibers. The vagus nerveleaves the cranium, passes down the neck within the carotid sheath tothe root of the neck, then passes to the chest and abdomen, where itcontributes to the innervation of the viscera.

A vagus nerve in man consists of over 100,000 nerve fibers (axons),mostly organized into groups. The groups are contained within fasciclesof varying sizes, which branch and converge along the nerve. Undernormal physiological conditions, each fiber conducts electrical impulsesonly in one direction, which is defined to be the orthodromic direction,and which is opposite the antidromic direction. However, externalelectrical stimulation of the nerve may produce action potentials thatpropagate in orthodromic and antidromic directions. Besides efferentoutput fibers that convey signals to the various organs in the body fromthe central nervous system, the vagus nerve conveys sensory (afferent)information about the state of the body's organs back to the centralnervous system. Some 80-90% of the nerve fibers in the vagus nerve areafferent (sensory) nerves, communicating the state of the viscera to thecentral nervous system.

The largest nerve fibers within a left or right vagus nerve areapproximately 20 μm in diameter and are heavily myelinated, whereas onlythe smallest nerve fibers of less than about 1 μm in diameter arecompletely unmyelinated. When the distal part of a nerve is electricallystimulated, a compound action potential may be recorded by an electrodelocated more proximally. A compound action potential contains severalpeaks or waves of activity that represent the summated response ofmultiple fibers having similar conduction velocities. The waves in acompound action potential represent different types of nerve fibers thatare classified into corresponding functional categories, withapproximate diameters as follows: A-alpha fibers (afferent or efferentfibers, 12-20 μm diameter), A-beta fibers (afferent or efferent fibers,5-12 μm), A-gamma fibers (efferent fibers, 3-7 μm), A-delta fibers(afferent fibers, 2-5 μm), B fibers (1-3 μm) and C fibers (unmyelinated,0.4-1.2 μm). The diameters of group A and group B fibers include thethickness of the myelin sheaths. It is understood that the anatomy ofthe vagus nerve is developing in newborns and infants, which accounts inpart for the maturation of autonomic reflexes. Accordingly, it is alsounderstood that the parameters of vagus nerve stimulation in the presentinvention are chosen in such a way as to account for this age-relatedmaturation [PEREYRA P M, Zhang W, Schmidt M, Becker L E. Development ofmyelinated and unmyelinated fibers of human vagus nerve during the firstyear of life. J Neurol Sci 110(1-2, 1992)107-113].

The waveforms disclosed in FIGS. 2A and 2B contain significant Fouriercomponents at high frequencies (e.g., 1/200 microseconds=5000/sec), evenif the waveform also has components at lower frequencies (e.g., 25/sec).Transcutaneously, A-beta, A-delta, and C fibers are typically excited at2000 Hz, 250 Hz, and 5 Hz, respectively, i.e., the 2000 Hz stimulus isdescribed as being specific for measuring the response of A-beta fibers,the 250 Hz for A-delta fibers, and the 5 Hz for type C fibers [George D.BAQUIS et al. TECHNOLOGY REVIEW: THE NEUROMETER CURRENT PERCEPTIONTHRESHOLD (CPT). Muscle Nerve 22(Supplement 8, 1999): S247-S259].Therefore, the high frequency component of the noninvasive stimulationwaveform will preferentially stimulate the A-alpha and A-beta fibers,and the C fibers will be largely unstimulated.

However, the threshold for activation of fiber types also depends on theamplitude of the stimulation, and for a given stimulation frequency, thethreshold increases as the fiber size decreases. The threshold forgenerating an action potential in nerve fibers that are impaled withelectrodes is traditionally described by Lapicque or Weiss equations,which describe how together the width and amplitude of stimulus pulsesdetermine the threshold, along with parameters that characterize thefiber (the chronaxy and rheobase). For nerve fibers that are stimulatedby electric fields that are applied externally to the fiber, as is thecase here, characterizing the threshold as a function of pulse amplitudeand frequency is more complicated, which ordinarily involves thenumerical solution of model differential equations or a case-by-caseexperimental evaluation [David BOINAGROV, Jim Loudin and DanielPalanker. Strength-Duration Relationship for Extracellular NeuralStimulation: Numerical and Analytical Models. J Neurophysiol 104(2010):2236-2248].

For example, REILLY describes a model (the spatially extended nonlinearnodal model or SENN model) that may be used to calculate minimumstimulus thresholds for nerve fibers having different diameters [J.Patrick REILLY. Electrical models for neural excitation studies. JohnsHopkins APL Technical Digest 9(1, 1988): 44-59]. According to REILLY'sanalysis, the minimum threshold for excitation of myelinated A fibers is6.2 V/m for a 20 μm diameter fiber, 12.3 V/m for a 10 μm fiber, and 24.6V/m for a 5 μm diameter fiber, assuming a pulse width that is within thecontemplated range of the present invention (1 ms). It is understoodthat these thresholds may differ slightly from those produced by thewaveform of the present invention as illustrated by REILLY's figures,for example, because the present invention prefers to use sinusoidalrather than square pulses. Thresholds for B and C fibers arerespectively 2 to 3 and 10 to 100 times greater than those for A fibers[Mark A. CASTORO, Paul B. Yoo, Juan G. Hincapie, Jason J. Hamann,Stephen B. Ruble, Patrick D. Wolf, Warren M. Grill. Excitationproperties of the right cervical vagus nerve in adult dogs. ExperimentalNeurology 227 (2011): 62-68]. If we assume an average A fiber thresholdof 15 V/m, then B fibers would have thresholds of 30 to 45 V/m and Cfibers would have thresholds of 150 to 1500 V/m. The present inventionproduces electric fields at the vagus nerve in the range of about 6 to100 V/m, which is therefore generally sufficient to excite allmyelinated A and B fibers, but not the unmyelinated C fibers. Incontrast, invasive vagus nerve stimulators that have been used for thetreatment of epilepsy have been reported to excite C fibers in somepatients [EVANS M S, Verma-Ahuja S, Naritoku D K, Espinosa J A.Intraoperative human vagus nerve compound action potentials. Acta NeurolScand 110 (2004): 232-238].

It is understood that although devices of the present invention maystimulate A and B nerve fibers, in practice they may also be used so asnot to stimulate the largest A fibers (A-delta) and B fibers. Inparticular, if the stimulator amplitude has been increased to the pointat which unwanted side effects begin to occur, the operator of thedevice may simply reduce the amplitude to avoid those effects. Forexample, vagal efferent fibers responsible for bronchoconstriction havebeen observed to have conduction velocities in the range of those of Bfibers. In those experiments, bronchoconstriction was only produced whenB fibers were activated, and became maximal before C fibers had beenrecruited [R. M. McALLEN and K. M. Spyer. Two types of vagalpreganglionic motoneurones projecting to the heart and lungs. J.Physiol. 282 (1978): 353-364]. Because proper stimulation with thedisclosed devices does not result in the side-effect ofbronchoconstriction, evidently the bronchoconstrictive B-fibers arepossibly not being activated when the amplitude is properly set. Also,the absence of bradycardia or prolongation of PR interval suggests thatcardiac efferent B-fibers are not stimulated. Similarly, A-deltaafferents may behave physiologically like C fibers. Because stimulationwith the disclosed devices does not produce nociceptive effects thatwould be produced by jugular A-delta fibers or C fibers, evidently theA-delta fibers may not be stimulated when the amplitude is properly set.

The use of feedback to generate the modulation signal 400 may result ina signal that is not periodic, particularly if the feedback is producedfrom sensors that measure naturally occurring, time-varying aperiodicphysiological signals from the patient (see FIG. 9). In fact, theabsence of significant fluctuation in naturally occurring physiologicalsignals from a patient is ordinarily considered to be an indication thatthe patient is in ill health. This is because a pathological controlsystem that regulates the patient's physiological variables may havebecome trapped around only one of two or more possible steady states andis therefore unable to respond normally to external and internalstresses. Accordingly, even if feedback is not used to generate themodulation signal 400, it may be useful to artificially modulate thesignal in an aperiodic fashion, in such a way as to simulatefluctuations that would occur naturally in a healthy individual. Thus,the noisy modulation of the stimulation signal may cause a pathologicalphysiological control system to be reset or undergo a non-linear phasetransition, through a mechanism known as stochastic resonance [B. SUKI,A. Alencar, M. K. Sujeer, K. R. Lutchen, J. J. Collins, J. S. Andrade,E. P. Ingenito, S. Zapperi, H. E. Stanley, Life-support system benefitsfrom noise, Nature 393 (1998) 127-128; W Alan C MUTCH, M Ruth Graham,Linda G Girling and John F Brewster. Fractal ventilation enhancesrespiratory sinus arrhythmia. Respiratory Research 2005, 6:41, pp. 1-9].

So, in one embodiment of the present invention, the modulation signal400, with or without feedback, will stimulate the selected nerve fibersin such a way that one or more of the stimulation parameters (power,frequency, and others mentioned herein) are varied by sampling astatistical distribution having a mean corresponding to a selected, orto a most recent running-averaged value of the parameter, and thensetting the value of the parameter to the randomly sampled value. Thesampled statistical distributions will comprise Gaussian and 1/f,obtained from recorded naturally occurring random time series or bycalculated formula. Parameter values will be so changed periodically, orat time intervals that are themselves selected randomly by samplinganother statistical distribution, having a selected mean and coefficientof variation, where the sampled distributions comprise Gaussian andexponential, obtained from recorded naturally occurring random timeseries or by calculated formula.

In another embodiment, devices in accordance with the present inventionare provided in a “pacemaker” type form, in which electrical impulses410 are generated to a selected region of the nerve by a stimulatordevice on an intermittent basis, to create in the patient a lowerreactivity of the nerve.

Preferred Dual-Electrode Embodiment of the Electrode-Based Stimulator

The electrodes of the invention are applied to the surface of the neck,or to some other surface of the body, and are used to deliver electricalenergy non-invasively to a nerve. The vagus nerve has been stimulatedpreviously non-invasively using electrodes applied via leads to thesurface of the skin. It has also been stimulated non-electricallythrough the use of mechanical vibration [HUSTON J M, Gallowitsch-PuertaM, Ochani M, Ochani K, Yuan R, Rosas-Ballina M et al (2007).Transcutaneous vagus nerve stimulation reduces serum high mobility groupbox 1 levels and improves survival in murine sepsis. Crit Care Med35:2762-2768; GEORGE M S, Aston-Jones G. Noninvasive techniques for probingneurocircuitry and treating illness: vagus nerve stimulation (VNS),transcranial magnetic stimulation (TMS) and transcranial direct currentstimulation (tDCS). Neuropsychopharmacology 35(1, 2010):301-316].However, no such reported uses of noninvasive vagus nerve stimulationwere directed to the treatment of headache sufferers. U.S. Pat. No.7,340,299, entitled Methods of indirectly stimulating the vagus nerve toachieve controlled asystole, to John D. PUSKAS, discloses thestimulation of the vagus nerve using electrodes placed on the neck ofthe patient, but that patent is unrelated to the treatment of headachesufferers. Non-invasive electrical stimulation of the vagus nerve hasalso been described in Japanese patent application JP2009233024A with afiling date of Mar. 26, 2008, entitled Vagus Nerve Stimulation System,to Fukui YOSHIHOTO, in which a body surface electrode is applied to theneck to stimulate the vagus nerve electrically. However, thatapplication pertains to the control of heart rate and is unrelated tothe treatment of headache sufferers. In patent publicationUS20080208266, entitled System and method for treating nausea andvomiting by vagus nerve stimulation, to LESSER et al., electrodes areused to stimulate the vagus nerve in the neck to reduce nausea andvomiting, but this too is unrelated to the treatment of headachesufferers.

Patent application US2010/0057154, entitled Device and method for thetransdermal stimulation of a nerve of the human body, to DIETRICH etal., discloses a non-invasive transcutaneous/transdermal method forstimulating the vagus nerve, at an anatomical location where the vagusnerve has paths in the skin of the external auditory canal. Theirnon-invasive method involves performing electrical stimulation at thatlocation, using surface stimulators that are similar to those used forperipheral nerve and muscle stimulation for treatment of pain(transdermal electrical nerve stimulation), muscle training (electricalmuscle stimulation) and electroacupuncture of defined meridian points.The method used in that application is similar to the ones used in U.S.Pat. No. 4,319,584, entitled Electrical pulse acupressure system, toMcCALL, for electroacupuncture; U.S. Pat. No. 5,514,175 entitledAuricular electrical stimulator, to KIM et al., for the treatment ofpain; and U.S. Pat. No. 4,966,164, entitled Combined sound generatingdevice and electrical acupuncture device and method for using the same,to COLSEN et al., for combined sound/electroacupuncture. A relatedapplication is US2006/0122675, entitled Stimulator for auricular branchof vagus nerve, to LIBBUS et al. Similarly, U.S. Pat. No. 7,386,347,entitled Electric stimulator for alpha-wave derivation, to CHUNG et al.,described electrical stimulation of the vagus nerve at the ear. Patentapplication US2008/0288016, entitled Systems and Methods for StimulatingNeural Targets, to AMURTHUR et al., also discloses electricalstimulation of the vagus nerve at the ear. U.S. Pat. No. 4,865,048,entitled Method and apparatus for drug free neurostimulation, toECKERSON, teaches electrical stimulation of a branch of the vagus nervebehind the ear on the mastoid processes, in order to treat symptoms ofdrug withdrawal. KRAUS et al described similar methods of stimulation atthe ear [KRAUS T, Hosl K, Kiess O, Schanze A, Kornhuber J, Forster C(2007). BOLD fMRI deactivation of limbic and temporal brain structuresand mood enhancing effect by transcutaneous vagus nerve stimulation. JNeural Transm 114: 1485-1493]. However, none of the disclosures in thesepatents or patent applications for electrical stimulation of the vagusnerve at the ear are used to treat headache sufferers.

Embodiments of the present invention may differ with regard to thenumber of electrodes that are used, the distance between electrodes, andwhether disk or ring electrodes are used. In preferred embodiments ofthe method, one selects the electrode configuration for individualpatients, in such a way as to optimally focus electric fields andcurrents onto the selected nerve, without generating excessive currentson the surface of the skin. This tradeoff between focality and surfacecurrents is described by DATTA et al. [Abhishek DATTA, Maged Elwassif,Fortunato Battaglia and Marom Bikson. Transcranial current stimulationfocality using disc and ring electrode configurations: FEM analysis. J.Neural Eng. 5 (2008): 163-174]. Although DATTA et al. are addressing theselection of electrode configuration specifically for transcranialcurrent stimulation, the principles that they describe are applicable toperipheral nerves as well [RATTAY F. Analysis of models forextracellular fiber stimulation. IEEE Trans. Biomed. Eng. 36 (1989):676-682].

A preferred embodiment of an electrode-based stimulator is shown in FIG.3. As shown in FIGS. 3A and 3B, the stimulator (30) comprises two heads(31) and a connecting part that joins them. Each head (31) contains astimulating electrode. The connecting part of the stimulator containsthe electronic components and battery (not shown) that are used togenerate the signals that drive the electrodes. However, in otherembodiments of the invention, the electronic components that generatethe signals that are applied to the electrodes may be separate, butconnected to the electrode head (31) using wires or wirelesscommunication with the heads. Furthermore, other embodiments of theinvention may contain a single such head or more than two heads.

Heads of the stimulator (31) are applied to a surface of the patient'sbody, during which time the stimulator may be held in place by straps orframes or collars, or the stimulator may be held against the patient'sbody by hand. In any case, the level of stimulation power may beadjusted with a wheel (34) that also serves as an on/off switch. A light(35) is illuminated when power is being supplied to the stimulator. Anoptional cap may be provided to cover each of the stimulator heads (31),to protect the device when not in use, to avoid accidental stimulation,and to prevent material within the head from leaking or drying. Thus, inthis embodiment of the invention, mechanical and electronic componentsof the stimulator (impulse generator, control unit, and power source)are compact, portable, and simple to operate.

Details of preferred embodiments of the stimulator heads are describedin co-pending, commonly assigned applications that were cited above. Asdescribed in those applications, the stimulator designs situate theelectrodes of the stimulator (340 in FIG. 1) remotely from the surfaceof the skin within a chamber, with conducting material (350 in FIG. 1)placed in a chamber between the electrode and the exterior component ofthe stimulator head that contacts the skin (351 in FIG. 1). One of thenovelties of this design is that the stimulator, along with acorrespondingly suitable stimulation waveform (see FIGS. 2A and 2B),shapes the electric field, producing a selective physiological responseby stimulating that nerve, but avoiding substantial stimulation ofnerves and tissue other than the target nerve, particularly avoiding thestimulation of nerves that produce pain. The term “shape an electricfield” as used herein means to create an electric field or its gradientthat is generally not radially symmetric at a given depth of stimulationin the patient, especially a field that is characterized as beingelongated or finger-like, and especially also a field in which themagnitude of the field in some direction may exhibit more than onespatial maximum (i.e. may be bimodal or multimodal) such that the tissuebetween the maxima may contain an area across which current flow isrestricted. Shaping of the electric field refers both to thecircumscribing of regions within which there is a significant electricfield and to configuring the directions of the electric field withinthose regions. Our invention does so by configuring elements that arepresent within equations that were disclosed in the commonly assignedco-pending application US20110230938 (application Ser. No. 13/075,746),entitled Device and methods for non-invasive electrical stimulation andtheir use for vagal nerve stimulation, to SIMON et al, which is herebyincorporated by reference.

FIG. 3A and FIG. 3B also shows a centerpiece 46 between the stimulatorheads 31, the outer surfaces of which all lie in a single plane, alongwhich the stimulator contacts the skin of the patient. Two versions ofthe centerpiece 46 are used. The version shown in FIGS. 3A and 3Bcontains an ultrasound transducer/probe 47 for imaging the patient'svagus nerve (or other target structure). The transducer/probe shownthere is a “hockey stick” style of probe, so-called because of itsshape, which is commercially available from most ultrasound machinemanufacturers. Thus, the ultrasound transducer that contacts the patientlies on the foot of the short end of the probe (its head), which isshown as the dark strip in 47 in FIG. 3A. The longer handle of the probe47 is show as protruding from the centerpiece 46 in the back view shownin FIG. 3B. The handle in turn connects to the ultrasound machine thatdisplays the anatomical structures that lie under the transducer. Thehead of the “hockey stick” style transducer/probe inserts securely intoa groove within the centerpiece 46, so as to make the linear transducerflat against the patient's skin and so as to lie within the plane of thesurface of the center of the electrode heads 31. By way of example, theHitachi Aloka UST-536 19 mm Hockey Stick style Transducer forsuperficial viewing has a frequency range of 6-13 MHz, a scan angle of90 degrees, and a scan width of 19 mm (Hitachi Aloka Medical America, 10Fairfield Boulevard, Wallingford Conn. 06492).

When a cervical vagus nerve is to be stimulated, the ultrasoundtransducer/probe 47 in the centerpiece 46 is used to determine theoptimum location to place the stimulator on the patient's neck. Oncethat location has been found, spots are marked on the patient's neck topreserve knowledge of the location, with the aid of “wormhole” ductsthat are situated within the centerpiece 46. One such duct is shownhaving an entrance port 48 on the side of the centerpiece and an exitport 49 that lies above the entrance port, on the top surface of thecenterpiece. When the stimulator is in its ideal position, a piece ofcotton attached to a flexible wire is dipped into a fluorescent dyesolution, which is then inserted into the entrance port and advancedthrough the duct until it reaches the exit port 49. At that point, thedye solution marks the location of the exit port by staining the skin ofthe patient. Preferably there are two or more such ducts within thecenterpiece 46. One of the exit ports 49 in FIG. 3A has a correspondingentrance port 48 that is shown in FIG. 3B.

Stimulators containing a second version of the centerpiece 46′ are usedafter the patient's skin has been marked with spots of dye that show theoptimal stimulator location. The second centerpiece version is shown inFIG. 3D. As seen there, the centerpiece 46′ does not contain anultrasound transducer/probe. Furthermore, it does not contain any“wormhole” duct as described above in connection with the centerpiece46. It does, however, contain apertures 49 that have the same positionsand registration as the exit ports 49 that were shown in FIG. 3A. Thecenterpiece 46′ also contains optical elements that cause thefluorescent spots on the patient's skin to fluoresce, when the apertures49 in FIG. 3D align with the spots on the patient's skin (i.e., when thestimulator is in its optimal position). Operation of the opticalelements shown in FIG. 3D are described below in connection with a morecomplete disclosure of methods for applying the stimulator to thepatient's neck.

Embodiment of the Vagus Nerve Stimulator with a Docking Station

In some embodiments of the nerve stimulator, all of its componentsreside in a single hand-held housing. In other embodiments, significantportions of the control of the vagus nerve stimulator may reside incontroller components that are physically separate from the housing forthe stimulator heads. Thus, some physically separate components of thecontroller and stimulator housing may generally communicate with oneanother wirelessly, thereby avoiding the inconvenience and distancelimitations of interconnecting cables.

A preferred embodiment of the invention with physically separatecomponents includes a docking station (40 in FIG. 3C) that may be usedas a recharging power supply for the stimulator housing (30 in FIG. 3),that may send/receive data to/from the stimulator housing, and that maysend/receive data to/from databases and other components of the system,including those that are accessible via the internet. Thus, prior to anyparticular stimulation session, the docking station may load into thestimulator parameters of the session, including waveform parameters. SeeFIGS. 2A and 2B and below for criteria used to select the parameters. Ina preferred embodiment, the docking station also limits the amount ofstimulation energy that may be consumed by the patient in the session bycharging the stimulator's rechargable battery with only a specifiedamount of releasable electrical energy, which is different than settinga parameter to restrict the duration of a stimulation session. As apractical matter, the stimulator housing may therefore use twobatteries, one for stimulating the patient (the charge of which may belimited by the docking station) and the other for performing otherfunctions such as data transmission. Methods for evaluating a battery'scharge or releasable energy are known in the art, for example, in U.S.Pat. No. 7,751,891, entitled Power supply monitoring for an implantabledevice, to ARMSTRONG et al. Alternatively, control components within thestimulator housing may monitor the amount of stimulation energy that hasbeen consumed during a stimulation session and stop the stimulationsession when a limit has been reached, irrespective of the time when thelimit has been reached.

The docking station is shown as item 40 in FIG. 3. The stimulatorhousing 30 and docking station 40 can be connect to one another byinserting the connector 36 near the center of the base 38 of thestimulator housing 30 into a mated connector 42 of the docking station40. As shown in FIG. 3, the docking station 30 has an indentation oraperture 41 that allows the base 38 of the stimulator housing 30 to beseated securely into the docking station. The connector 36 of thestimulator housing is recessed in an aperture 37 of the base of thestimulator housing 30 that may be covered by a detachable or hingedcover when the stimulator housing is not attached to the docking station(not shown).

The mated connectors 36 and 42 have a set of contacts that have specificfunctions for the transfer of power to charge a rechargable battery inthe stimulator housing 30 and to transfer data bidirectionally betweenthe stimulator housing and docking station. As a safety feature, thecontacts at the two ends of the mated connector are connected to oneanother within the stimulator housing and within the docking station,such that if physical connection is not made at those end contacts, allthe other contacts are disabled via active switches. Also, theconnectors 36 and 42 are offset from the center of the base 38 of thestimulator housing 30 and from the center of the indentation or aperture41 of the docking station 40, so that the stimulator housing can beinserted in only one way into the docking station. That is to say, whenthe stimulator housing 30 is attached to the docking station 40, thefront of the stimulator housing 30 must be on the front side of thedocking station 40. As shown, the back side of the docking station hasan on/off switch 44 and a power cord 43 that attaches to a wall outlet.The docking station 40 also has ports (e.g., USB ports) for connectingto other devices, one of which 45 is shown on the side of the station,and others of which are located on the front of the station (not shown).The front of the docking station has colored lights to indicatatewhether the docking station has not (red) or has (green) charged thestimulator so as to be ready for a stimulation session.

Through cables to the communication port 45, the docking station 40 cancommunicate with the different types of devices, such as thoseillustrated in FIG. 4. Handheld devices may resemble conventional remotecontrols with a display screen (FIG. 4A) or mobile phones (FIG. 4B).Other type of devices with which the docking station may communicate aretouchscreen devices (FIG. 4C) and laptop computers (FIG. 4D).

The communication connections between different components of thestimulator's controller are shown in FIG. 5, which is an expandedrepresentation of the control unit 330 in FIG. 1. Connection between thedocking station controller components 332 and components within thestimulator housing 331 is denoted in FIG. 5 as 334. For example, thatconnection is made when the stimulator housing is connected to thedocking station as described above. Connection between the dockingstation controller components 332 and devices 333 such as those shown inFIG. 4 (generally internet-based components) is denoted as 335.Connection between the components within the stimulator housing 331 anddevices 333 such as those shown in FIG. 4 (generally internet-basedcomponents) is denoted as 336. Different embodiments of the inventionmay lack one or more of the connections. For example, if the connectionbetween the stimulator housing and the devices 333 is only through thedocking station controller components, then in that embodiment of theinvention, only connections 334 and 335 would be present.

The connections 334, 335 and 336 in FIG. 5 may be wired or wireless. Forexample, if the controller component 333 is the mobile phone shown inFIG. 4B, the connection 335 to a docking station port (45 in FIG. 3)could be made with a cable to the phone's own docking port. Similarly,if the controller component 333 is the laptop computer shown in FIG. 4D,the connection 335 to a docking station port (45 in FIG. 3) could bemade with a cable to a USB port on the computer. However, the preferredconnections 334, 335, and 336 will be wireless.

Although infrared or ultrasound wireless control might be used tocommunicate between components of the controller, they are not preferredbecause of line-of-sight limitations. Instead, in the presentdisclosure, the communication between devices preferably makes use ofradio communication within unlicensed ISM frequency bands (260-470 MHz,902-928 MHz, 2.400-2.4835 GHz). Components of the radio frequency systemin devices in 331, 332, and 333 typically comprise a system-on-chiptransciever with an integrated microcontroller; a crystal; associatedbalun & matching circuitry, and an antenna [Dag GRINI. RF Basics, RF forNon-RF Engineers. Texas Instruments, Post Office Box 655303, Dallas,Tex. 75265, 2006].

Transceivers based on 2.4 GHz offer high data rates (greater than 1Mbps) and a smaller antenna than those operating at lower frequencies,which makes them suitable for with short-range devices. Furthermore, a2.4 GHz wireless standard (Bluetooth, Wi-Fi, and ZigBee) may be used asthe protocol for transmission between devices. Although the ZigBeewireless standard operates at 2.4 GHz in most jurisdictions worldwide,it also operates in the ISM frequencies 868 MHz in Europe, and 915 MHzin the USA and Australia. Data transmission rates vary from 20 to 250kilobits/second with that standard. Because many commercially availablehealth-related sensors may operate using ZigBee, its use may berecommended for applications in which the controller uses feedback andfeedforward methods to adjust the patient's vagus nerve stimulationbased on the sensors' values, as described below in connection with FIG.9 [ZigBee Wireless Sensor Applications for Health, Wellness and Fitness.ZigBee Alliance 2400 Camino Ramon Suite 375 San Ramon, Calif. 94583].

A 2.4 GHz radio has higher power consumption than radios operating atlower frequencies, due to reduced circuit efficiencies. Furthermore, the2.4 GHz spectrum is crowded and subject to significant interference frommicrowave ovens, cordless phones, 802.11b/g wireless local areanetworks, Bluetooth devices, etc. Sub-GHz radios enable lower powerconsumption and can operate for years on a single battery. Thesefactors, combined with lower system cost, make sub-GHz transceiversideal for low data rate applications that need maximum range andmulti-year operating life.

The antenna length needed for operating at different frequencies is 17.3cm at 433 MHz, 8.2 cm at 915 MHz, and 3 cm at 2.4 GHz. Therefore, unlessthe antenna is included in a neck collar that supports the device shownin FIG. 3A, the antenna length may be a disadvantage for 433 MHztransmission. The 2.4 GHz band has the advantage of enabling one deviceto serve in all major markets worldwide since the 2.4 GHz band is aglobal spectrum. However, 433 MHz is a viable alternative to 2.4 GHz formost of the world, and designs based on 868 and 915 MHz radios can servethe US and European markets with a single product.

Range is determined by the sensitivity of the transceiver and its outputpower. A primary factor affecting radio sensitivity is the data rate.Higher data rates reduce sensitivity, leading to a need for higheroutput power to achieve sufficient range. For many applications thatrequire only a low data rate, the preferred rate is 40 Kbps where thetransceiver can still use a standard off-the-shelf 20 parts per millioncrystal.

A typical signal waveform that might be transmitted wirelessly to thestimulator housing (30 in FIG. 3) was shown in FIGS. 2B and 2C. As seenthere, individual sinusoidal pulses have a period of tau, and a burstconsists of N such pulses. This is followed by a period with no signal(the inter-burst period). The pattern of a burst followed by silentinter-burst period repeats itself with a period of T. For example, thesinusoidal period tau may be 200 microseconds; the number of pulses perburst may be N=5; and the whole pattern of burst followed by silentinter-burst period may have a period of T=40000 microseconds, which iscomparable to 25 Hz stimulation (a much smaller value of T is shown inFIG. 2C to make the bursts discernable). When these exemplary values areused for T and tau, the waveform contains significant Fourier componentsat higher frequencies ( 1/200 microseconds=5000/sec). Such a signal maybe easily transmitted using 40 Kbps radio transmission. Compression ofthe signal is also possible, by transmitting only the signal parameterstau, N, T, E_(max), etc., but in that case the stimulator housing'scontrol electronics would then have to construct the waveform from thetransmitted parameters, which would add to the complexity of componentsof the stimulator housing (30 in FIG. 3).

However, because it is contemplated that sensors attached to thestimulator housing may also be transmitting information, such asaccelerometers that are used to detect motion of the stimulator relativeto the vagus nerve, the data transfer requirements may be substantiallygreater than what is required only to transmit the signal shown in FIG.2A-2C. Electromyographic and electroglottographic data may also need tobe transmitted, as described below. Therefore, the present invention maymake use of any frequency band, not limited to the ISM frequency bands,as well as techniques known in the art to suppress or avoid noise andinterferences in radio transmission, such as frequency hopping anddirect sequence spread spectrum.

Application of the Stimulator to the Neck of the Patient

Selected nerve fibers are stimulated in different embodiments of methodsthat make use of the disclosed electrical stimulation devices, includingstimulation of the vagus nerve at a location in the patient's neck. Atthat location, the vagus nerve is situated within the carotid sheath,near the carotid artery and the interior jugular vein. The carotidsheath is located at the lateral boundary of the retopharyngeal space oneach side of the neck and deep to the sternocleidomastoid muscle. Theleft vagus nerve is sometimes selected for stimulation becausestimulation of the right vagus nerve may produce undesired effects onthe heart, but depending on the application, the right vagus nerve orboth right and left vagus nerves may be stimulated instead.

The three major structures within the carotid sheath are the commoncarotid artery, the internal jugular vein and the vagus nerve. Thecarotid artery lies medial to the internal jugular vein, and the vagusnerve is situated posteriorly between the two vessels. Typically, thelocation of the carotid sheath or interior jugular vein in a patient(and therefore the location of the vagus nerve) will be ascertained inany manner known in the art, e.g., by feel or ultrasound imaging.Proceeding from the skin of the neck above the sternocleidomastoidmuscle to the vagus nerve, a line may pass successively through thesternocleidomastoid muscle, the carotid sheath and the internal jugularvein, unless the position on the skin is immediately to either side ofthe external jugular vein. In the latter case, the line may passsuccessively through only the sternocleidomastoid muscle and the carotidsheath before encountering the vagus nerve, missing the interior jugularvein. Accordingly, a point on the neck adjacent to the external jugularvein might be preferred for non-invasive stimulation of the vagus nerve.The magnetic stimulator coil may be centered on such a point, at thelevel of about the fifth to sixth cervical vertebra.

FIG. 6A illustrates use of the device 30 shown in FIG. 3 to stimulatethe vagus nerve at that location in the neck, in which the stimulatordevice 30 is shown to be applied to the target location on the patient'sneck as described above. For reference, FIG. 6A shows the locations ofthe following vertebrae: first cervical vertebra 71, the fifth cervicalvertebra 75, the sixth cervical vertebra 76, and the seventh cervicalvertebra 77.

FIG. 6B shows the locations of additional electrodes that may be placedon the surface of the neck. The approximate location of a pair ofelectrodes 80 that may be used for electroglottography is shown, as wellas a pair of electrode arrays 81 that may be used for laryngealelectromyography (L-EMG). Use of these additional electrodes isdiscussed in paragraphs below. Because electroglottography useselectrodes on both sides of the neck, the outer surface of heads of thevagus nerve stimulator 31 may serve as electroglottographic electrodeson the right side of the neck as shown, or separate electrodes 82 may beused for that purpose. Electronics for the electroglottographic andL-EMG methods are housed within the vagus nerve stimulator 30, so leadwires 83 connect the electrodes 80, 81 and 82 (if present) to thestimulator 30. Sinusoidal signals applied to the electroglottograpicelectrodes are typically in the range 300 kHz to 5 MHz. This frequencyis sufficiently high that the current capacitively bypasses the lessconductive skin layer, without the need for using conductive electrodegel or paste. Dry electrodes may also be used for the electromyography[MERLETTI R, Botter A, Troiano A, Merlo E, Minetto M A. Technology andinstrumentation for detection and conditioning of the surfaceelectromyographic signal: state of the art. Clin Biomech (Bristol, Avon)24(2, 2009)122-134].

The additional electrodes and their lead wires may be attachedskin-side-up to the inner surface of a collar, so as to help maintainthem in their correct position. FIG. 7 shows the stimulator 30 appliedto the neck of a child, which is partially immobilized with a foamcervical collar 78 that is similar to ones used for neck injuries andneck pain. The collar is tightened with a strap 79, and the stimulatoris inserted through a hole in the collar to reach the child's necksurface. As shown, the stimulator is turned on and off with a controlknob, and the amplitude of stimulation may also be adjusted with thecontrol knob that is located on the stimulator. In other models, thecontrol knob is absent or disabled, and the stimulator may be turned onand off remotely, using a wireless controller that may be used to adjustthe stimulation parameters of the controller (e.g., on/off, stimulationamplitude, frequency, etc.).

FIG. 8 provides a more detailed view of use of the electrical stimulator30, when positioned to stimulate the vagus nerve at the neck locationthat is indicated in FIG. 6. The vagus nerve 60 is identified in FIG. 8,along with the carotid sheath 61 that is identified there in boldperipheral outline. The carotid sheath encloses not only the vagusnerve, but also the internal jugular vein 62 and the common carotidartery 63. Features that may be identified near the surface of the neckinclude the external jugular vein 64 and the sternocleidomastoid muscle65. Additional organs in the vicinity of the vagus nerve include thetrachea 66, thyroid gland 67, esophagus 68, scalenus anterior muscle 69,and scalenus medius muscle 70. The sixth cervical vertebra 76 is alsoshown in FIG. 8, with bony structure indicated by hatching marks.

Methods of treating a patient comprise stimulating the vagus nerve asindicated in FIGS. 6 and 7, using the electrical stimulation devicesthat are disclosed here. Before stimulation is performed, the neck iscleaned but not abraded, and depending on the individual, hair may havebeen previously removed by conventional epilation methods (e.g., waxingor electrology). Stimulation may be performed on the left or right vagusnerve or on both of them simultaneously or alternately. The location ofa vagus nerve underlying the stimulator may be determined preliminarilyby imaging with the ultrasound probe 47 in FIGS. 3A and 3B [KNAPPERTZ VA, Tegeler C H, Hardin S J, McKinney W M. Vagus nerve imaging withultrasound: anatomic and in vivo validation. Otolaryngol Head Neck Surg118(1, 1998):82-85; GIOVAGNORIO F and Martinoli C. Sonography of thecervical vagus nerve: normal appearance and abnormal findings. AJR Am JRoentgenol 176(3, 2001):745-749]. On transverse scans, the vagus nervehas a honeycomb appearance with 2 to 4 hypoechoic rounded fasciclessurrounded by a hyperechoic epineurium. To the extent that there isvariation in the distance between the skin and vagus nerve as a functionof position up and down the neck, the stimulator should be positioned insuch a way that the distance is minimized.

The stimulator should also be positioned in such a way that the nerve islocated in the center of the ultrasound image, taking into account thefact that in approximately 5 percent of individuals, the vagus nerve hasan unusual anatomical course that is possibly associated with abnormalthyroid gland anatomy. Also, the vagus nerve of approximately 25% ofindividuals has an atypical position within the carotid sheath [GIBSONA. Bilateral abnormal relationship of the vagus nerve in its cervicalportion. J Anat Physiol 49 (1915):389-392; TUBBS R S, Loukas M, Shoja MM, Blevins D, Humphrey R, Chua G D, Kelly D R, Oakes W J. An unreportedvariation of the cervical vagus nerve: anatomical and histologicalobservations. Folia Morphol (Warsz) 66(2, 2007):155-157; PARK J K, JeongS Y, Lee J H, Lim G C, Chang J W. Variations in the course of thecervical vagus nerve on thyroid ultrasonography. AJNR Am J Neuroradiol32(7, 2011):1178-1181; DIONIGI G, Chiang F Y, Rausei S, Wu C W, Boni L,Lee K W, Rovera F, Cantone G, Bacuzzi A. Surgical anatomy andneurophysiology of the vagus nerve (VN) for standardized intraoperativeneuromonitoring (IONM) of the inferior laryngeal nerve (ILN) duringthyroidectomy. Langenbecks Arch Surg 395(7, 2010):893-899]. In additionto an unusual anatomical course of the vagus nerve, the ultrasoundimaging may also reveal potential problems such as inflammation of thenerve that may contraindicate the use of vagus nerve stimulation [EinarP V WILDER-SMITH. Nerve Ultrasound: Ready for clinical practice?Neurology Asia 17(1, 2012):1-4].

As part of the preliminary protocol, the patient is instructed or helpedto perform neck movements, to breathe deeply so as to contract thesternocleidomastoid muscle, and generally to simulate possible motionthat may accompany prolonged stimulation with the stimulator. Thestimulator is maintained firmly in place against the neck as themovements are made, such that the stimulator will also experience somemovement. Straps, harnesses, collars, or frames may be used to maintainthe stimulator in position. The movement of the stimulator is monitoredusing miniature three-axis accelerometers (possibly with combinedgyroscopes) that are embedded in the body of the stimulator (forexample, Model LSM330DL from STMicroelectronics, 750 Canyon Dr #300Coppell, Tex. 75019). Such an accelerometer is situated in each of thetwo simulator heads (31 in FIG. 3), and another accelerometer issituated in the vicinity of the bottom of the stimulator (38 in FIG. 3).While these movements are being performed, the accelerometers areacquiring position information, and the corresponding location of thevagus nerve is determined from the ultrasound image. With thesepreliminary data, it is then possible to infer the location of the vagusnerve relative to the stimulator, given only the accelerometer dataduring a stimulation session, by interpolating between the previouslyacquired vagus nerve position data as a function of accelerometerposition data.

Actual nerve stimulation is then performed with a sinusoidal burstwaveform like that shown in FIGS. 2A-2C. The pattern of a burst followedby silent inter-burst period repeats itself with a period of T. Forexample, the sinusoidal period τ may be 200 microseconds; the number ofpulses per burst may be N=5; and the whole pattern of burst followed bysilent inter-burst period may have a period of T=40000 microseconds,which is comparable to 25 Hz stimulation. More generally, there may be 1to 20 pulses per burst, preferably five pulses. Each pulse within aburst has a duration of 1 to 1000 microseconds (i.e., about 1 to 10KHz), preferably 200 microseconds (about 5 KHz). A burst followed by asilent inter-burst interval repeats at 1 to 5000 bursts per second(bps), preferably at 5-50 bps, and even more preferably 10-25 bpsstimulation (10-25 Hz). The preferred shape of each pulse is a fullsinusoidal wave, although triangular or other shapes may be used aswell.

The amplitude of the stimulation is initially increased until thepatient first perceives stimulation when current is passed through thestimulator electrodes. The applied current is increased gradually, to alevel wherein the patient feels constant sensation from the stimulation.The power may then be increased even more, but is set to a level that isless than one at which the patient first indicates any discomfort. Thestimulator signal may have a frequency and other parameters that areselected to produce a therapeutic result in the patient, i.e.,stimulation parameters for each patient are adjusted on anindividualized basis. Ordinarily, the amplitude of the stimulationsignal is set to the maximum that is comfortable for the patient, andthen the other stimulation parameters are adjusted. Preferably,ultrasound imaging of the nerve is also performed when the nerve ispreliminarily stimulated electrically, because the stimulation may alsocause contraction of nearby muscle (e.g., sternocleidomastoid muscle),which may necessitate some repositioning of the stimulator in order tomaintain the nerve in the center of the ultrasound image [IRIARTE J,Artieda J, Alegre M, Schlumberger E, Urrestarazu E, Pastor M A, ViteriC. Spasm of the sternocleidomastoid muscle induced by vagal nervestimulation. Neurology 57(12, 2001):2319-2320].

Methods and Devices for Evaluating whether the Vagus Nerve is BeingStimulated

The question then arises as to whether the sensation that the patientexperiences is due to stimulation of the vagus nerve at a givenstimulation amplitude, or whether much of the sensation is due primarilyto the stimulation of tissue closer to the skin, such as muscle and skinitself. If the latter were the case, then any therapeutic results fromusing the vagus nerve stimulator would likely be attributable only to aplacebo effect [R WENNBERG. Short term benefit of battery depletion invagus nerve stimulation for epilepsy. J Neurol Neurosurg Psychiatry75(6, 2004): 939]. Therefore, tests are performed to determine whetherthe vagus nerve is in fact being stimulated, one of which is as follows.The human vagus nerve is supplied by a distinct vagal artery and veinthat lie on the anterior aspect of the nerve [FERNANDO D A, Lord R S.The blood supply of vagus nerve in the human: its implication in carotidendarterectomy, thyroidectomy and carotid arch aneurectomy. Ann Anat176(4, 1994):333-337]. When the vagus nerve is electrically stimulated,its metabolic needs increase, such that there is reflex-increased bloodflow within the vagal artery and its associated arterioles. Thus, onetest for whether the vagus nerve is being stimulated is to measure bloodflow in the vagal artery and compare it with the flow when the vagusnerve is not being stimulated. KNAPPERTZ et al (cited above) were unableto delineate the vagal artery with color flow Doppler ultrasoundimaging. However, conventional Doppler-based imaging techniques areunable to detect low velocity blood flow in smaller vessels, the chiefdifficulty being that blood is a weak reflector of ultrasound. Onemethod to overcome this difficulty is to inject brighter ultrasoundreflectors than blood into the vascular system. Gas filled microbubblesare one such reflector or contrast agent. Therefore, according to thepresent invention, one method for demonstrating stimulation of a vagusnerve is to measure an increased (or conceivably decreased) vagal arteryblood flow, preferably using ultrasound contrast agents [Matthew BRUCE,Mike Averkiou, and Jeff Powers. Ultrasound contrast in general imagingresearch. (2007). Philips Medical Systems, Global Information Center,P.O. Box 1286, 5602 BG Eindhoven, The Netherlands, pp. 1-19].

The stimulation vs. non-stimulation issue has also been raised by otherinvestigators in connection with implanted vagus nerve stimulators, butto date there is no agreed upon method for verifying stimulation of thevagus nerve. Furthermore, the methods that have been proposed forverifying the stimulation of an implanted stimulator may not be relevantto the present invention involving non-invasive stimulation. Forexample, operation of an implanted vagus nerve stimulator may beverified by placing measurement electrodes on the patient's skin abovethe implant [U.S. Pat. No. 7,228,167, entitled Method and apparatus fordetecting vagus nerve stimulation, to KARA et al]. However, in thepresent invention there are already electrodes placed on the skin abovethe vagus nerve to perform the stimulation noninvasively, in lieu ofstimulating at an internal site. Therefore, in the present invention,subsurface electrical properties within the patient's tissue following askin-surface electrical stimulation pulse would have to be inferred fromskin-surface electrical measurements by estimating currents under theskin, using electrical impedance tomography, electrical resistivitytomography, induced polarization, spectral induced polarization andrelated electrical pulse-response methods. Field equations that may beused for that purpose were disclosed in co-pending, commonly assignedapplication Ser. No. 13/075,746, entitled DEVICES AND METHODS FORNON-INVASIVE ELECTRICAL STIMULATION AND THEIR USE FOR VAGAL NERVESTIMULATION ON THE NECK OF A PATIENT, to SIMON et al, which is herebyincorporated by reference. The use of such methods for demonstratingaltered subsurface electrical properties (including electrical changesat a vagus nerve) requires the solution of inverse mathematicalequations, which is greatly aided by the availability of a priorianatomical information that is provided by ultrasound imaging, performedas described above.

Other methods for verifying and monitoring stimulation of the vagusnerve are described in paragraphs that follow. In general, they rely onthe stimulated vagus nerve causing some physiological response that canbe measured, such as some change in the autonomic nervous system, anevoked potential, changes in the chemistry of the blood, or changes inblood flow within the brain that can be measured using PET or functionalmagnetic resonance imaging [HENRY T R. Therapeutic mechanisms of vagusnerve stimulation. Neurology 59(6 Suppl 4, 2002):53-514]. Preferably,the measured physiological response is one that is mechanisticallyrelated to the disease that is being treated. For example, if thepatient is a migraine sufferer, the physiological signal may be onerelated to asymmetric responses of the autonomic nervous system, asevidenced by differences such as left versus right eye pupil responses[HARLE D E, Wolffsohn J S, Evans B J. The pupillary light reflex inmigraine. Ophthalmic Physiol Opt 25(3, 2005):240-245].

However, more generally, disease-related responses to vagus nervestimulation may be slow to occur, and if the patient is being treatedwith vagus nerve stimulation as a prophylaxis, such responses might beindistinguishable from those experienced by a normal individual.Consequently, when the initial goal is to demonstrate simply that thevagus nerve is in fact being stimulated with a particular stimulationamplitude and other stimulation parameters, usefulness of the test maybe evaluated primarily on the basis of the sensitivity of thetest-physiological system to vagus nerve stimulation. In devising such asensitive test, one may look to the physiological systems that are mostoften perturbed as side effects of vagus nerve stimulation. Forimplanted vagus nerve stimulators, side-effects that are unrelated tothe implantation surgery itself (e.g., incision pain) occur with thefollowing frequency, as reported by a stimulator device manufacturer:voice alteration (33%), pharyngitis (inflammation of the throat) (13%),dysphagia (difficulty swallowing) (11%), hypesthesia (numbness) (11%),nausea (9%), dyspnea (shortness of breath) (9%), headache (8%), neckpain (7%), increased cough (6%), paresthesia (6%) [Depression Patient'sManual for Vagus Nerve Stimulation with the VNS Therapy System. DocumentREF 26-0005-6000/1, 2004. Cyberonics Inc. 100 Cyberonics Boulevard,Houston, Tex. U.S.A. 77058]. Other investigators report similarfindings, except that 55 percent of the patients experienced voicealteration, and a significant number of patients experience arrhythmiasas well, possibly because of more relaxed patient exclusion criteria[SACKEIM H A, Rush A J, George M S, Marangell L B, Husain M M, Nahas Z,Johnson C R, Seidman S, Giller C, Haines S, Simpson R K Jr, Goodman R R.Vagus nerve stimulation (VNS) for treatment-resistant depression:efficacy, side effects, and predictors of outcome.Neuropsychopharmacology 25(5, 2001):713-728]. Other investigators reporteven higher percentages of side-effects related to the patient's voiceand larynx. SANTOS reported that 66 percent of patients undergoinginvasive vagus nerve stimulation therapy exhibit changes to their vocalfold (vocal cord) functioning, even though not all such patients sensethat there has been voice change [SANTOS P M. Evaluation of laryngealfunction after implantation of the vagus nerve stimulation device.Otolaryngol Head Neck Surg 129(3, 2003):269-273]. CHAROUS et al foundthat 95 percent of patients undergoing invasive vagus nerve stimulationhave voice changes when the stimulator is first activated [CHAROUS S J,Kempster G, Manders E, Ristanovic R. The effect of vagal nervestimulation on voice. Laryngoscope 111(11 Pt 1, 2001):2028-2031]. ZALVANet al found that 100% of such patients exhibit laryngeal dysfunction[ZALVAN C, Sulica L, Wolf S, Cohen J, Gonzalez-Yanes O, Blitzer A.Laryngopharyngeal dysfunction from the implant vagal nerve stimulator.Laryngoscope 113(2, 2003):221-225]. In fact, voice alteration inpatients with implanted vagus nerve stimulators is so common thatdevices have been disclosed that turn off the stimulator when thepatient is speaking [U.S. Pat. No. 5,205,285, entitled Voice suppressionof vagal stimulation, to BAKER, Jr.].

In view of these data, voice alteration is by far the most commonside-effect of vagus nerve stimulation, suggesting that tests of thepatient's voice are likely to demonstrate that the vagus nerve is beingstimulated. Physiologically, this is understandable because therecurrent laryngeal nerve, a branch of the vagus nerve, enervatesmuscles of the focal folds (vocal cords) of the larynx and would beexpected to be stimulated as a component of the cervical vagus nerve.Accordingly, the first tests for vagus nerve stimulation that aredisclosed below are voice-related. Note, however, that some of thelaryngeal side-effects that have accompanied vagus nerve stimulationwith implanted stimulators may be due to the fact that the types ofpatients undergoing the treatment (e.g., epileptics) are also treatedwith certain drugs that appear to cause dysfunction of the larynx evenbefore the vagus nerve stimulator is implanted [SHAW G Y, Sechtem P,Searl J, Dowdy E S. Predictors of laryngeal complications in patientsimplanted with the Cyberonics vagal nerve stimulator. Ann Otol RhinolLaryngol 115(4, 2006):260-267]. Furthermore, vagus nerve stimulatorimplantation may damage the vagus nerve, through mishandling of thenerve during the implantation and through electrode migration,inflammatory reaction to a foreign body, and the nature of electricalstimulation from the implanted electrode itself. Therefore, the effectson the larynx from invasive stimulation of the vagus nerve, particularlyin patients without epilepsy, would not necessarily correspond to theeffects on the larynx found in patients whose vagus nerve is stimulatednoninvasively [TRAN Y, Shah A K, Mittal S. Lead breakage and vocal cordparalysis following blunt neck trauma in a patient with vagal nervestimulator. J Neurol Sci 304(1-2, 2011):132-135].

Some details concerning the effects on the larynx from invasive vagusnerve stimulation have been identified, through use of general methodsthat are used by otolaryngologists and speech pathologists to evaluatevoice pathology. Understanding of those methods and their resultsrequires some background concerning the physiology of the larynx andvocal folds, as follows. The function of the larynx is to modulate theflow and pressure of air entering and leaving the lungs and lowerairway. Within the larynx, the glottis is the primary area of control,consisting of the vocal folds (vocal cords or plicae vocals) and thevariable gap between them (the rima glottidis). Airflow is regulateddifferently by the glottis during respiration, coughing, swallowing, andvocalization.

Mechanical support for the larynx (voicebox) at the top of the tracheaconsists of several cartilaginous structures, including the thyroid,cricoid, arytenoid, cuneiform, corniculate, and epiglottis cartilages.The vocal folds (vocal cords) consist of a pair of infoldings of mucousmembrane stretched horizontally across the larynx, attached posteriorlyto the arytenoid cartilages, and anteriorly to the thyroid cartilage.When the vocal folds are juxtaposed to one another (adducted), they canvibrate as air is expelled from the lungs, producing speech sounds.During inhalation, they are open (abducted) to allow the free passage ofair. Adduction and abduction of the vocal folds are controlled bylaryngeal muscles [C. A. ROSEN and C. B. Simpson. Anatomy and physiologyof the larynx. Chapter 1 (pp. 3-8). In: C Blake Simpson and Clark ARosen, Operative Techniques in Laryngology. Berlin: Springer, 2008;SATALOFF R T, Heman-Ackah Y D, Hawkshaw M J. Clinical anatomy andphysiology of the voice. Otolaryngol Clin North Am 40(5, 2007):909-929].

Nuanced control of the laryngeal muscles, ultimately by higher centersof the brain that also control respiration, the lips, and tongue,results in coherent speech [BROWN S, Ngan E, Liotti M. A larynx area inthe human motor cortex. Cereb Cortex 18(4, 2008):837-845]. That centralcontrol of the laryngeal muscles involves not only feedback from sensorynerves within the larynx, tongue, and other airway structures, but alsofeedback involving the sounds that the speaker hears from his or her ownspeech [LUDLOW C L. Central nervous system control of the laryngealmuscles in humans. Respir Physiol Neurobiol 147(2-3, 2005):205-222;VANDAELE D J, Cassell M D. Multiple forebrain systems converge on motorneurons innervating the thyroarytenoid muscle. Neuroscience 162(2,2009):501-524; CHANG E F, Niziolek C A, Knight R T, Nagarajan S S, HoudeJ F. Human cortical sensorimotor network underlying feedback control ofvocal pitch. Proc Natl Acad Sci USA. 110(7, 2013):2653-2658; SayakoMASUDA, Naomi Sakai and Koichi Mori. Neural basis underlying vocal andspeech control using auditory feedback. Chapter 11 (pp. 115-125) In:Shigeru Watanabe (ed). CARLS Series of Advanced Study of Logic andSensibility, Volume 2. Tokyo: Keio University Press (2008); SUSSMAN H M.What the tongue tells the brain. Psychol Bull 77(4, 1972):262-272].

The muscles of the larynx are classified as either intrinsic (confinedto the larynx) or extrinsic (attaching the larynx to other structureswithin the head and neck). Vocal fold movements produced by thesemuscles may be described as adductor (vocal fold closing) and abductor(opening). Intrinsic laryngeal muscles are usually classified as havingeither an adductor action (thyroarytenoid, lateral cricoarytenoid andinterarytenoid muscles) or abductor function (posterior cricoarytenoidmuscle). The cricothyroid muscle, on the other hand, is an intrinsicmuscle that serves a different function, namely, to elongate the vocalfolds. In addition to the intrinsic muscles, there are also severalextrinsic laryngeal muscles that act in concert to provide laryngealstabilization, but they only indirectly affect the position of the vocalfolds.

These intrinsic laryngeal muscles are controlled by the right and leftvagus nerves, each of which descends in a carotid sheath giving offthree major branches: the pharyngeal branch, the superior laryngealnerve (SLN), and the recurrent laryngeal nerve (RLN). The RLN arisesfrom the vagus nerve in the upper chest and loops under the aortic arch(left) or subclavian artery (right), and ascends back into the neck,entering the larynx posteriorly. The RLN innervates the ipsilateralposterior cricoarytenoid muscle, the interarytenoid muscle, and thelateral cricoarytenoid muscle, and terminates in the thyroarytenoidmuscle. Thus, the RLN supplies all of the intrinsic laryngeal muscleswith the exception of the cricothyroid muscle. Muscle innervation isunilateral, except for the interarytenoid muscle, which receivescontributions from both left and right RLNs. Consequently, stimulationof a cervical vagus nerve, which branches into the RLN below the site ofstimulation, can be expected primarily to modulate the activity of thesemuscles ipsilaterally, which in turn influences activity of thecorresponding vocal fold. To limit the possibility of stimulating thevocal folds, one could stimulate the vagus nerve distal to the RLN farbelow the neck, but even then the vocal folds might be stimulatedindirectly via afferent vagal nerves that send signals to the brainstemand then to the laryngeal center of the brain [PublicationUS20110301658, entitled Spatially selective vagus nerve stimulation, toYOO et al]. Otherwise, minimizing the effect of vagus nerve stimulationon the larynx would rely on selecting the stimulation parameters withthat goal in mind [Publication 20110301659, entitled Vagus nervestimulation with target effects controlled by adjusting temporalparameters, to YOO et al; YOO P B, Hincapie J G, Hamann J J, Ruble S B,Wolf P D, Grill W M. Selective control of physiological responses bytemporally-patterned electrical stimulation of the canine vagus nerve.Conf Proc IEEE Eng Med Biol Soc. 2011; 2011:3107-3110].

The SLN supplies sensation to the larynx, as well as motor input to thecricothyroid muscle, which controls vocal fold lengthening and pitch.Whereas invasive vagus nerve stimulation would not be expected tostimulate the SLN, because the SLN has branched from the vagus nerve atthe level of the C1 and C2 vertebra before reaching the site of theimplanted electrode, the less localized noninvasive vagus nervestimulation could conceivably stimulate a branch of the SLN as itdescends to the vicinity of the thyroid gland. The anatomical course ofthe SLN is variable, and damage to the SLN (as well as the RLN) is amajor risk factor in thyroid surgery. Considering that the thyroid gland(67 in FIG. 8) is relatively close to the vagus nerve (60 in FIG. 8),which may itself occupy an abnormal location within the carotid sheath,direct noninvasive stimulation of the SLN might occur in some patients[FRIEDMAN M, LoSavio P, Ibrahim H. Superior laryngeal nerveidentification and preservation in thyroidectomy. Arch Otolaryngol HeadNeck Surg 128(3, 2002):296-303]. However, both invasive and noninvasivevagus nerve stimulation might also result in an indirect stimulation ofthe SLN, as well as stimulation of a contralateral laryngeal nerve. Thisis because the electrical stimulation might result in afferent vagalsignals that reach the brainstem and brain, which in turn result in theproduction of SLN motor signals, as well as contralateral RLN motorsignals [LUDLOW C L. Central nervous system control of the laryngealmuscles in humans. Respir Physiol Neurobiol 147(2-3, 2005):205-222;ORDELMAN S C, Kornet L, Cornelussen R, Buschman H P, Veltink P H. Anindirect component in the evoked compound action potential of the vagalnerve. J Neural Eng 7(6, 2010):066001: pp 1-9]. However, such laryngealreflex signals have been sought, but have not yet been observed [Y00 PB,Lubock N B, Hincapie J G, Ruble S B, Hamann J J, Grill W M.High-resolution measurement of electrically-evoked vagus nerve activityin the anesthetized dog. J Neural Eng 10(2, 2013):026003: pp. 1-9].

Damage to the RLN and/or SLN may result in vocal paralysis or paresis.Such damage is not uncommon in patients who have implanted vagus nervestimulators [SHAFFER M J, Jackson C E, Szabo C A, Simpson C B. Vagalnerve stimulation: clinical and electrophysiological effects on vocalfold function. Ann Otol Rhinol Laryngol 114(1 Pt 1, 2005):7-14; SHAW GY, Sechtem P, Searl J, Dowdy E S. Predictors of laryngeal complicationsin patients implanted with the Cyberonics vagal nerve stimulator. AnnOtol Rhinol Laryngol 115(4, 2006):260-267; GHANEM T, Early S V. Vagalnerve stimulator implantation: an otolaryngologist's perspective.Otolaryngol Head Neck Surg 135(1, 2006):46-51; ZALVAN C, Sulica L, WolfS, Cohen J, Gonzalez-Yanes O, Blitzer A. Laryngopharyngeal dysfunctionfrom the implant vagal nerve stimulator. Laryngoscope 113(2,2003):221-225; HOERTH M, Drazkowski J, Sirven J, Hinni M, Smith B,Labiner D. Vocal cord paralysis after vagus nerve stimulator batteryreplacement successfully treated with medialization thyroplasty. ClinNeurol Neurosurg 109(9, 2007):788-790; KALKANIS J G, Krishna P, EspinosaJ A, Naritoku D K. Self-inflicted vocal cord paralysis in patients withvagus nerve stimulators. Report of two cases. J Neurosurg 96(5,2002):949-951]. Vocal fold paralysis implies vocal fold immobility dueto neurologic injury. Vocal fold paresis implies vocal fold hypomobilitydue to neurologic injury and may result from weak muscular stimulationby the RLN, SLN, or both. Vocal fold paresis may present as dysphonia,loss of the upper register of the voice, hoarseness, breathiness, throatpain, choking episodes, or decreased vocal stamina. Clinically,unilateral RLN injury presents as a breathy voice. After a few weeks,the contralateral vocal fold may compensate by adducting further toimprove vocal quality and aspiration. Injury to an SLN manifests itselfmost clearly as a change in voice range. In SLN paresis and paralysis,the loss of function may lead to lowered pitch, a more monotone voice,and poor vocal performance at higher pitches. SLN paresis and paralysismay also cause vocal fatigue, hoarseness, impairment of volume, loss ofupper range, loss of projection, and breathiness [RUBIN A D, Sataloff RT. Vocal fold paresis and paralysis. Otolaryngol Clin North Am 40(5,2007):1109-1131; SULICA L, Blitzer A. Vocal fold paresis: evidence andcontroversies. Curr Opin Otolaryngol Head Neck Surg 15(3, 2007):159-162;KOUFMAN J A, Postma G N, Cummins M M, Blalock P D. Vocal fold paresis.Otolaryngol Head Neck Surg 122(4, 2000):537-541].

In view of the fact that vocal paralysis or paresis may be caused by animplanted vagus nerve stimulator, U.S. Pat. Nos. 7,801,603 and8,290,584, both entitled Method and apparatus for optimizing vagal nervestimulation using laryngeal activity, to WESTLUND et al. appear to belimited in their application, as now explained. Their disclosureincludes “an activity indicative of laryngeal activity” and “a neuralstimulation input indicative of stimulation of a vagus nerve”. Arationale of their disclosure is that “vagal nerve stimulation causesvibration of the larynx through the recurrent laryngeal nerves . . . .Thus, laryngeal activity, including the magnitude and frequency of thevibration of the larynx, provides for an indication of whether the vagusnerve is activated by the neural stimulation. This allows foroptimization of therapy without the need to monitor and analyze thetarget response (such as cardiac remodeling) of the vagal nervestimulation”. “The activity sensor . . . is placed on the neck over thelarynx to sense a signal indicative of laryngeal activity,” which issaid to be an accelerometer. An application of the system is said to be“optimization of electrode placement”, which presumably takes placeduring the surgical implantation of a vagus nerve stimulator while thepatient is anesthetized. In fact, nowhere in the disclosure does itindicate that the patient voluntarily participates in activating thelarynx, for example, through vocalization, which may be an advantageduring surgery. It is possible that the larynx may vibrate as aconsequence of the vagus nerve stimulation, as disclosed by WESTLUND etal, and this effect is used in devices that stimulate the vagus nerve totreat voice problems [e.g., U.S. Pat. No. 7,069,082, entitled Pacemakerfor bilateral vocal cord autoparalysis, to LINDENTHALER; U.S. Pat. No.7,840,280, entitled Cranial nerve stimulation to treat a vocal corddisorder, to PARNIS et al]. However, the above-cited referencesconcerning vocal paralysis and paresis resulting from vagus nervestimulation demonstrate that such stimulation may also inhibit ratherthan activate vibration of the larynx. Therefore, WESTLUND et al havenot disclosed a general method for detecting whether the vagus nerve isbeing sufficiently stimulated “for optimization of therapy without theneed to monitor and analyze the target response.” The same critiqueapplies to devices that use implanted or external mechanical sensorsother than an accelerometer, such as a microphone or pressure sensor[Publication US20120172741, entitled Systems and methods for usingsensed pressure for neuro-cardiac therapy, to ARCOT-KRISHNAMURTHY etal].

Systems that replace such a mechanical sensor with an electrical sensorof laryngeal muscle activity (essentially laryngeal electromyography, orL-EMG) may work more reliably in detecting activity of the vagus nerve[U.S. Pat. No. 5,111,814, entitled Laryngeal pacemaker, to GOLDFARB;Publication US20110313483 entitled Methods and apparatus for controllingneurostimulation using evoked responses, to HINCAPIE-ORDONEZ et al.;US20130053926, entitled Systems to detect vagus capture, toHINCAPIE-ORDONEZ et al; SHAFFER M J, Jackson C E, Szabo C A, Simpson CB. Vagal nerve stimulation: clinical and electrophysiological effects onvocal fold function. Ann Otol Rhinol Laryngol 114(1 Pt 1, 2005):7-14;ARDESCH J J, Sikken J R, Veltink P H, van der Aa H E, Hageman G,Buschman H P. Vagus nerve stimulation for epilepsy activates the vocalfolds maximally at therapeutic levels. Epilepsy Res 89(2-3,2010):227-231]. In practice they are similar to conventional LEMGmethods, except that a vagus nerve is stimulated invasively, rather thanthe standard LEMG method of stimulating the spinal accessory nerve. Theyare also similar to methods used during thyroid and brainstem surgery tomonitor the integrity of a vagus nerve, using EMG of a laryngeal muscleas a safety indicator, some of which place the EMG electrode on anendotracheal tube [SEVERTSON M A, Leonetti J P, Jarocki D. Vagal nervemonitoring: a comparison of techniques in a canine model. Am J Otol18(3, 1997):398-400; FRIEDRICH C, Ulmer C, Rieber F, Kern E, Kohler A,Schymik K, Thon K P, Lamade W. Safety analysis of vagal nervestimulation for continuous nerve monitoring during thyroid surgery.Laryngoscope 122(9, 2012):1979-1987; DIONIGI G, Chiang F Y, Rausei S, WuC W, Boni L, Lee K W, Rovera F, Cantone G, Bacuzzi A. Surgical anatomyand neurophysiology of the vagus nerve (VN) for standardizedintraoperative neuromonitoring (IONM) of the inferior laryngeal nerve(ILN) during thyroidectomy. Langenbecks Arch Surg 395(7, 2010):893-899;PHELAN E, Potenza A, Slough C, Zurakowski D, Kamani D, Randolph G.Recurrent laryngeal nerve monitoring during thyroid surgery: normativevagal and recurrent laryngeal nerve electrophysiological data.Otolaryngol Head Neck Surg 147(4, 2012):640-646; SINGH R, Husain A M.Neurophysiologic intraoperative monitoring of the glossopharyngeal andvagus nerves. J Clin Neurophysiol. 2011 December; 28(6, 2011):582-586].

However, these EMG methods suffer from the disadvantage that in order towork best, they require the invasive placement of an electrode into alaryngeal muscle [HEMAN-ACKAH Y D, Sataloff R T. Laryngeal EMG: BasicConcepts and Clinical Uses. Journal of Singing 2002; 58(3):233-238].Interpretation of such laryngeal EMG signals is also problematic,because virtually every author to address the subject of vocal paresishas remarked on the discrepancy of clinical observations andelectromyographic findings [SULICA L, Blitzer A. Vocal fold paresis:evidence and controversies. Curr Opin Otolaryngol Head Neck Surg 15(3,2007):159-162]. For example, it is not uncommon for paresis to bestrongly suggested by visual laryngeal examination, but theelectromyographic signals are normal in all muscles tested. Thediscrepancy may be because each electrode track gives only a limitedpicture of the activity of the whole muscle, such that theelectromyographic electrode would have to be placed at multiplelocations within the muscle in order to obtain an accuraterepresentation of nerve-muscle interaction. Furthermore, the signals areinfluenced by many different confounding activities (e.g., phonating,sniffing, breathing, or swallowing).

According to the present invention, there is a better way to useelectromyographic measurements in order to demonstrate that the vagusnerve is being stimulated. The disclosed method relies not onelectromyographic measurement per se, but instead relies upon the factthat the electromographic signals should be asymmetric when comparingleft versus right muscles. This is because the vagus nerve stimulationis being performed on one side of the neck, so there should be alteredlaryngeal muscle activity primarily on the ipsilateral side but not onthe contralateral side, when the vagus nerve is stimulated. With this inmind, one may use surface electromyographic recordings instead ofinvasive (intramuscular) recordings, in which the surface EMG electrodesneed not be attached to a tracheal tube. Rather than attempt to obtainEMG recordings from separate laryngeal muscles, surface electrodes areplaced symmetrically on both sides of the larynx, possibly overlyingmultiple laryngeal muscles [neck surface locations are illustrated byHIRANO M, Ohala J. Use of hooked-wire electrodes for electromyography ofthe intrinsic laryngeal muscles. J Speech Hear Res 12(2, 1969):362-373].Preferably electrode arrays are used. For example, a pair ofelectromyographic electrode arrays 81 is shown in FIG. 6B. Before thevagus nerve is stimulated electrically, when speech is performed (seeHIRANO), the signals across the two arrays behave in a symmetric manner,so as to be able to make correspondence between particular arrayelements in the two arrays [MERLETTI R, Botter A, Troiano A, Merlo E,Minetto M A. Technology and instrumentation for detection andconditioning of the surface electromyographic signal: state of the art.Clin Biomech (Bristol, Avon) 24(2, 2009):122-134]. Then, as vagusstimulation is applied and its amplitude is increased, the signals fromcorresponding array elements in the two arrays should becomeincreasingly dissimilar or asymmetric during speech or other laryngealactivity, by virtue of the fact the vagus nerve stimulation is affectinglaryngeal muscles primarily or preferentially on the ipsilateral side ofthe larynx. Thus, in the present invention it is the magnitude of theasymmetry of the EMG signals that is used as an indication of vagusnerve stimulation, rather than the EMG signals per se, even in thepresence of confounding simultaneous activity (e.g., phonating,sniffing, breathing, or swallowing). For example, for corresponding left(L) and right (R) array element electromyographic measurement values,the differences with and without nerve stimulation at voltage V may becalculated (Lv−Lo and Rv−Ro), and an asymmetry index for that elementmay be constructed, such as [(Lv−Lo)/(Lv+Lo)]−[(Rv−Ro)/(Rv+Ro)]. Anoverall asymmetry index may be calculate from the individual arrayindices, such as the array element index having the greatest absolutevalue or the average of all array element indices.

Laryngeal electromyography is one of many techniques that are used toassess or diagnose voice or larynx disorders [Ronald J BAKEN and RobertF Orlikoff. Clinical measurement of speech and voice. Second edition.Clifton Park, N.Y.: Delmar Cengage Learning, 2010; DEJONCKERE P H,Bradley P, Clemente P, et al. A basic protocol for functional assessmentof voice pathology, especially for investigating the efficacy of(phonosurgical) treatments and evaluating new assessment techniques.Guideline elaborated by the Committee on Phoniatrics of the EuropeanLaryngological Society (ELS). Eur Arch Otorhinolaryngol 258(2,2001):77-82]. The techniques include performing a spectral analysis ofthe patient's speech or otherwise performing a time-series analysis ofspoken audio signals, laryngoscopic visualization of the vocal foldsincluding high speed cinematography, stroboscopy of the vocal folds,optical measurement of glottis opening, electrical measurement ofglottis opening (electroglottography), the measurement of air pressurein regions of the vocal tract, the measurement of airflow as it relatesto the aerodynamics of sound generation, and measurements involving thenose, pharynx, and tongue-palate.

The time series analysis of spoken acoustic signals often presupposesthat the signal is stationary and periodic, resulting from phonation ofa sustained vowel at a constant pitch and intensity level. However,other voice types also exist, namely bifurcating, chaotic and stochastictypes [Alicia SPRECHER, Aleksandra Olszewski, and Jack J. Jiang.Updating signal typing in voice: Addition of type 4 signals. J AcoustSoc Am 127(6, 2010): 3710-3716]. To produce periodic acoustic voicesignals, the patient is placed in a quiet room, an omnidirectionalmicrophone is placed at a fixed distance from the patient's mouth (e.g.16 cm), and the patient produces a sustained vowel such as /a/ or /i/ ata loudness and pitch that is comfortable at approximately conversationallevel. The patient may be provided with earplugs to prevent auditoryfeedback from influencing the speech. The signal from the microphone isdigitized at about 20 to 40 kHz at 16 bits and is then analyzed bycomputer to calculate acoustic indices. Traditional measurements includeFO (the fundamental frequency or pitch of vocal oscillation), absolutesound pressure level (indicating the relative loudness of speech),jitter (the extent of variation in speech F0 from vocal cycle to vocalcycle), shimmer (the extent of variation in speech amplitude from cycleto cycle), and noise-to-harmonics ratios (the amplitude of noiserelative to tonal components in the speech) [Will STYLER. Using Praatfor Linguistic Research. Boulder, Colo.: University of Colorado atBoulder Phonetics Lab, University of Colorado Linguistics Department,295 UCB, Boulder Colo. 80309, 2103. pp. 1-70]. In addition to theseclassical acoustic characterizations of voice, nonlinear dynamicalindices have also been calculated, such as the correlation dimension andLyapunov exponent [Max A. LITTLE, Declan A. E. Costello, and Meredydd L.Harries. Objective dysphonia quantification in vocal fold paralysis:comparing nonlinear with classical measures. J Voice 25(1, 2011): 21-31;Max A LITTLE, Patrick E McSharry, Stephen J Roberts, Declan A ECostello, and Irene M Moroz. Exploiting nonlinear recurrence and fractalscaling properties for voice disorder detection. Biomed Eng Online.2007; 6: 23. pp. 1-35].

Such classical, but not nonlinear, acoustic indices have been measuredfrom the voices of patients stimulated by an implanted vagus nervestimulator. However, for reasons described above, it is not clear thatthese results would apply also to noninvasive vagus nerve stimulation.LUNDY et al found that the indices vary as a function of the vagus nervestimulation frequency. However, LUNDY et al did not vary the amplitudeof the nerve stimulation systematically, so it is not clear howsensitive the indices are to detecting the onset of laryngeal effects.They also measured cardiorespiratory variables but apparently found nosignificant effects on heartrate or other cardiorespiratory indices[LUNDY D S, Casiano R R, Landy H J, Gallo J, Gallo B, Ramsey R E.Effects of vagal nerve stimulation on laryngeal function. J Voice 7(4,1993):359-364]. CHAROUS et al reported changes in classical acousticparameters when the vagus nerve was stimulated, but they did notindicate any of nerve stimulation parameters such as nerve stimulationfrequency [CHAROUS S J, Kempster G, Manders E, Ristanovic R. The effectof vagal nerve stimulation on voice. Laryngoscope 111(11 Pt 1,2001):2028-2031]. KERSING et al also reported changes in classicalacoustic parameters when the vagus nerve was stimulated. The stimulationwas performed at 30 Hz, and the amplitude of stimulation was increasedvery slowly over the course of many weeks, during which time the larynxwould be adapting to the increased amplitude [KERSING W, Dejonckere P H,van der Aa H E, Buschman H P. Laryngeal and vocal changes during vagusnerve stimulation in epileptic patients. J Voice 16(2, 2002):251-257].

Because KERSING et al increased the amplitude so gradually, it is notclear how sensitive any of the acoustic indices would be in detectingthe onset of laryngeal effects when the vagus nerve stimulation is firstapplied. ZUMSTEG et al reported that in some patients, laryngeal effectscan be detected even at very small vagus nerve stimulation amplitudes,but those effects were observed visually, not through use of anyacoustic measurement [ZUMSTEG D, Jenny D, Wieser H G. Vocal cordadduction during vagus nerve stimulation for treatment of epilepsy.Neurology 54(6, 2000)1388-1389]. In view of the limitations of the datathat have been reported to date, what is needed is a demonstrativelysensitive acoustic method for detecting laryngeal effects from verylow-amplitude vagus nerve stimulation, even before any effect becomesclearly noticeable by the patient or bystander. LITTLE et al reportedthat nonlinear acoustic indices perform at least as well as theclassical acoustic indices, but they have not been calculated usingvoice signals of patients treated with invasive vagus nerve stimulation[Max A. LITTLE, Declan A. E. Costello, and Meredydd L. Harries.Objective dysphonia quantification in vocal fold paralysis: comparingnonlinear with classical measures. J Voice 25(1, 2011):21-31].

In the present context, use of the above-mentioned classical andnonlinear acoustic indices to infer vagus nerve stimulation suffers fromtwo deficiencies. The first is that they make no use of a prioriinformation concerning the asymmetry of vocal fold stimulation, namely,that the vagus nerve stimulation is affecting laryngeal musclesprimarily or preferentially on the ipsilateral side of the larynx. Thesecond is that they are limited to situations in which the spoken soundis stationary and periodic, i.e., the patient produces a sustainedvowel, which derives from a bias on the part of laryngologists that theywould also like to be able to view the vocal folds under a conditionsuitable for stroboscopic viewing. To address these deficiencies, in thepresent invention, the patient is also instructed to perform amonotonous pitch raise, wherein the patient phonates a vowel such as /a/from a low pitch up to a much higher one. Such a maneuver has been usedin connection with visualization of the vocal folds, but has apparentlynever been performed purely for acoustic voice analysis [WURZBACHER T,Schwarz R, Dollinger M, Hoppe U, Eysholdt U, Lohscheller J. Model-basedclassification of nonstationary vocal fold vibrations. J Acoust Soc Am120(2, 2006):1012-1027]. Under such a monotonous pitch raise speechpattern, the effects of laryngeal asymmetries are much more likely to bepronounced, and at some places in the pitch rise, significant deviationsfrom regular periodicity may become apparent, such as biphonation orsubharmonic oscillation [EYSHOLDT U, Rosanowski F, Hoppe U. Vocal foldvibration irregularities caused by different types of laryngealasymmetry. Eur Arch Otorhinolaryngol 260(8, 2003):412-417; MAUNSELL R,Ouaknine M, Giovanni A, Crespo A. Vibratory pattern of vocal folds undertension asymmetry. Otolaryngol Head Neck Surg 135(3, 2006):438-444;SIMPSON C B, May L S, Green J K, Eller R L, Jackson C E. Vibratoryasymmetry in mobile vocal folds: is it predictive of vocal fold paresis?Ann Otol Rhinol Laryngol 120(4, 2011):239-242; STEINECKE I, Herzel H.Bifurcations in an asymmetric vocal-fold model. J Acoust Soc Am 97(3,1995):1874-1884; XUE Q, Mittal R, Zheng X, Bielamowicz S. Acomputational study of the effect of vocal-fold asymmetry on phonation.J Acoust Soc Am 128(2, 2010):818-827].

To analyze such a monotonous pitch raise speech pattern (continuousglissando), and optionally a subsequent monotonous pitch decrease speechpattern, the speech is digitized as described above for a sustainedvowel; the time-series is broken into many time segments; and theabove-described classical and nonlinear speech indices are calculatedfor each of them. Less common measurements are also made, particularlyestimation of the relative power in the first five individual harmonicfrequencies, as a complement to the more traditional harmonics-to-noiseratio measurement. Preferably the acoustic signal is nearly stationarywithin each segment, but if it is not, then either shorter time-segmentsare used, or the data are detrended within the segment before performingthe index calculations. Therefore, the method produces a set ofsequences of classical and nonlinear acoustic parameters, which may beinterpolated to produce a set of continuous acoustic parameters as afunction of time.

The objective in acquiring these monotonous pitch raise (and optionallydescending) data is to develop a method that can distinguish betweensituations in which the noninvasive vagus nerve stimulator is actuallystimulating a vagus nerve, versus situations in which it is not. To thatend, the procedure described in the previous paragraph is performed withthe stimulator applied to the patient's neck, but with differentstimulation amplitudes, starting with the control of no stimulation.Thus, one acquires sets of data with which to train a classifier which,after it is trained, can attempt to predict whether an unknown set ofdata was acquired when nerve stimulation was applied using some non-zerostimulation amplitude. If the classification (stimulation vs. nostimulation) can be made correctly more than some specified percentageof the time (say, 95%), then the data plus the classifier constitute areliable method for evaluating whether the vagus nerve is beingstimulated. The preferred classifier is a support vector machine (SVM),which is an algorithmic approach to the problem of classification withinthe larger context of supervised learning. A number of classificationproblems whose solutions in the past have been solved by multi-layerback-propagation neural networks, or more complicated methods, have beenfound to be more easily solvable by SVMs [Christopher J. C. BURGES. Atutorial on support vector machines for pattern recognition. Data Miningand Knowledge Discovery 2 (1998), 121-167; J. A. K. SUYKENS, J.Vandewalle, B. De Moor. Optimal Control by Least Squares Support VectorMachines. Neural Networks 14 (2001):23-35; SAPANKEVYCH, N. and Sankar,R. Time Series Prediction Using Support Vector Machines: A Survey. IEEEComputational Intelligence Magazine 4(2, 2009): 24-38; PRESS, W H;Teukolsky, S A; Vetterling, W T; Flannery, B P (2007). Section 16.5.Support Vector Machines. In: Numerical Recipes: The Art of ScientificComputing (3rd ed.). New York: Cambridge University Press]. Preferably,the training of the SVM is performed using data from the patient forwhom the stimulation decision is to be ultimately made, but training ofthe SVM may also be attempted using acoustic data obtained from multiplepatients.

The set of acoustic data may also be supplemented with simultaneouslyacquired electroglottographic data as follows, so as to improve theaccuracy and sensitivity of the SVM classification (stimulation vs. nostimulation). Electroglottography (EGG) provides information about theclosure of vocal folds by measuring the electrical impedance between two(or more) electrodes, placed on the surface of the neck on oppositesides of the larynx [U.S. Pat. No. 4,139,732, entitled Apparatus forspeech pattern derivation, to FOURCIN; Adrian FOURCIN. Precisionstroboscopy, voice quality and electrolaryngography. Chapter 13 in: KentR. D. and Ball M. J. (eds) Voice Quality Measurement' (2000) San Diego:Singular Publishing Group, pp 1-32]. The approximate location on oneside of the neck of a pair of electrodes 80 that may be used forelectroglottography is shown in FIG. 6B. In this embodiment, two pairsof electrodes are used, as described by ROTHENBERG [U.S. Pat. No.4,909,261, entitled Tracking multielectrode electroglottograph, toROTHENBERG; Martin ROTHENBERG. A Multichannel Electroglottograph.Journal of Voice 6(1, 1992):36-43]. Because electroglottography needselectrodes on both sides of the neck, the outer surface of electrodeswithin heads of the vagus nerve stimulator 31 in FIG. 6B may serve aselectroglottographic electrodes on the right side of the neck as shown,or separate electrodes 82 may be used for that purpose. Electronics forthe electroglottography are housed within the vagus nerve stimulator 30,so lead wires 83 connect the electrodes 80 and 82 (if present) to thestimulator 30. Sinusoidal signals applied to the electroglottograpicelectrodes produced by the stimulator 30 are typically in the range 300kHz to 5 MHz. This frequency is sufficiently high that the currentcapacitively bypasses the less conductive skin layer, without the needfor using conductive electrode gel or paste. Those high frequency, verylow amplitude signals are superimposed upon signals that are used forthe vagus nerve stimulation itself. Exemplary circuits for measuring theimpedance are described by SARVAIYA et al [SARVAIYA J N, Pandey P C,Pandey V K. An impedance detector for glottography. IETE J Res 55(2009):100-105].

The impedance varies as the space in between the vocal folds (the rimaglottidis) opens (increased impedance) and closes (decreased impedance)during each vocal cycle. Alteration of other structures of the larynx inrelation to one another will also cause the impedance to fluctuate, forexample, as the entire larynx is raised, lowered, and tilted. The EGGdata may be acquired as a time series by digitizing at 20 to 40 kHz at16 bits, then processed with computer programs to extract informationabout laryngeal function. EGG calculations typically estimate thecontact phase of the vibratory cycle, such as the contact quotient (CQ),or evaluate the geometry of the waveform itself [TITZE I R.Parameterization of the glottal area, glottal flow, and vocal foldcontact area. J Acoust Soc Am 75(2, 1984):570-580]. Indices that areused for acoustic waveforms may also be calculated with EGG data (e.g.,jitter, shimmer) [Nathalie HENRICH, Cedric Gendrot and Alexis Michaud.Tools for Electroglottographic Analysis: Software, Documentation andDatabases. Web page archived by the WayBack Machine at the domainvoiceresearch.free.fr under the subdomain/egg, pp. 1-4; MartinROTHENBERG and James J. Mashie. Monitoring vocal fold abduction throughvocal fold contact area. Journal of Speech and Hearing Research 31(1988): 338-351]. Abnormal EGGs are characterized by patterns resemblingsine waves that may have a superimposed short (contact) peak and may beused to predict whether laryngeal electromyograms will be abnormal aswell [MAYES R W, Jackson-Menaldi C, Dejonckere P H, Moyer C A, Rubin AD. Laryngeal electroglottography as a predictor of laryngealelectromyography. J Voice 22(6, 2008):756-759].

In the present application involving the support vector machineclassification of signals involving monotonous pitch raise (and optionalsubsequent pitch lowering), the entire signal is broken into segments aswith the acoustic signal, and parameters are calculated for eachsegment. Therefore, the method produces a set of sequences of EGGparameters, which may be interpolated to produce a set of continuous EGGparameters as a function of time. These time series are provided to theSVM for training and eventually classification, along with the acousticdata. As the patient changes his or her pitch, the EGG data should beparticularly useful for detecting transitions between different forms ofphonation, the details of which may be sensitive to the presence ofvagus nerve stimulation. Thus, as the patient raises his or her pitchslowly, the larynx shifts from one vocal mode to another at particularfrequencies, analogous to an automobile shifting gears, and according tothe present invention, the frequencies at which those transitions occurmay change depending on the amplitude of vagus nerve stimulation[Nathalie HENRICH, Bernard Roubeau and Michele Castellengo. On the useof electroglottography for characterization of the laryngeal mechanism.Proceedings of the Stockholm Music Acoustics Conference, Aug. 6-9, 2003(SMAC 03), Stockholm, Sweden, pp. 1-4].

Laryngeal electromyographic L-EMG data as a function of time may also beprovided to the support vector machine classifier along with the otherdata, acquired using electrode arrays 81 shown in FIG. 6B. As describedabove, the L-EMG data will be in the form of indices of asymmetrybetween corresponding left and right array elements. Although it is notspecifically related to laryngeal function, time-series data describingthe respiratory cycle may also be provided to the classifier, becauserespiration is a part of phonation. The acquisition of a respiratorysignal is described below in connection with the use of control-theorymethods.

Many other measurements have been suggested for monitoring the effectsof stimulating the vagus nerve. For example, FRIEDRICH et al decidedthat in addition to measurement of laryngeal EMG, heart rate variabilityand TNF-alpha blood concentration measurements were also to be made, asan indication of effects of the vagus nerve stimulation on the autonomicnervous system and on immunomodulation, respectively [FRIEDRICH C, UlmerC, Rieber F, Kern E, Kohler A, Schymik K, Thon K P, Lamade W. Safetyanalysis of vagal nerve stimulation for continuous nerve monitoringduring thyroid surgery. Laryngoscope 122(9, 2012):1979-1987]. Thepresent invention may also make use of autonomic nervous systemmeasurement, which may be used individually or as part of the set ofdata that are provided to a support vector machine for deciding whetherthe vagus nerve is being stimulated. The rationale for using autonomicindices is that a primary proximate effect of stimulating a vagus nerveis to alter parasympathetic tone, and alteration of sympathetic tonewill follow as a consequence. As described below, the autonomic indicesthat are preferably measured involve electrodermal responses, heart ratevariability and responses related to the control of pupil diameter andblood flow to the eye.

Electrodermal activity (EDA) is due to sweat that is secreted by eccrinesweat glands and excreted through sweat ducts. Secretion by sweat glandsis under the control of sympathetic nerves, and consequently, EDA servesas a surrogate of the activity of the sympathetic nervous system, asinfluenced by central nervous system components [Wolfram BOUCSEIN.Electrodermal activity, 2nd Ed., New York: Springer, 2012, pp. 1-618;Hugo D. CRITCHLEY. Electrodermal responses: what happens in the brain.Neuroscientist 8(2, 2002):132-142; Michael E. DAWSON, Anne M. Schell andDiane L. Filion. The electrodermal system. In: John T. Cacioppo, LouisG. Tassinary and Gary G. Berntson, eds. Handbook of Psychophysiology,2nd. Ed., Cambridge, UK: Cambridge University press, 2000, Chapter 8,pp. 200-223; FREDRIKSON M, Furmark T, Olsson M T, Fischer H, AnderssonJ, Langstrom B. Functional neuroanatomical correlates of electrodermalactivity: a positron emission tomographic study. Psychophysiology 35(2,1998):179-85; Henrique SEQUEIRA, Pascal Hot, Laetitia Silvert, SylvainDelplanque. Electrical autonomic correlates of emotion. InternationalJournal of Psychophysiology 71 (2009): 50-56].

Ordinarily, electrodermal measurement is made on the palm, volar side ofa finger, or feet of a patient, although measurement at other sites suchas the shoulder may be useful as well [Marieke van DOOREN, J. J. G.(Gert-Jan) de Vries, Joris H. Janssen. Emotional sweating across thebody: Comparing 16 different skin conductance measurement locations.Physiology & Behavior 106 (2012): 298-304]. Since 1981, a particularskin conductance method has been the international standard technique torecord and analyze electrodermal activity (EDA) [Wolfram BOUCSEIN.Electrodermal activity, 2nd Ed., New York: Springer, 2012, pp. 1-618].In the present application of determining whether the vagus nerve hasbeen stimulated, the EDA response is measured immediately before,during, and following the nerve stimulation. Miniature electrodermalsensors have become available for use in ambulatory monitoring, whichare particularly useful when used in conjunction with an accelerometer[Ming-Zher P O H, Nicholas C. Swenson, and Rosalind W. Picard. Awearable sensor for unobtrusive, long-term assessment of electrodermalactivity. IEEE Transactions on Biomedical Engieering 57(5,2010):1243-1252; Ming-Zher P O H, Tobias Loddenkemper, Nicholas C.Swenson, Shubhi Goyal, Joseph R. Madsen and Rosalind W. Picard.Continuous monitoring of electrodermal activity during epilepticseizures using a wearable sensor. 32nd Annual International Conferenceof the IEEE EMBS, Buenos Aires, Argentina, Aug. 31-Sep. 4, 2010, pp.4415-4418; Ming-Zher P O H, Tobias Loddenkemper, Claus Reinsberger,Nicholas C. Swenson, Shubhi Goyal, Mangwe C. Sabtala, Joseph R. Madsen,and Rosalind W. Picard. Convulsive seizure detection using a wrist-wornelectrodermal activity and accelerometry biosensor. Epilepsia 53(5,2012):e93-e97]. Preferably, the electrodermal activity is measured onboth sides of the body, so that indices of asymmetry may be calculatedas described above in connection with the laryngeal electromyographydata.

Several non-invasive measurements other than electrodermal activity canalso be used to assess sympathetic activity in a patient, and they mayprovide an indication of parasympathetic activity as well [MENDES, W. B.Assessing the autonomic nervous system. Chapter 7 In: E. Harmon-Jonesand J. Beer (Eds.) Methods in Social Neuroscience. New York: GuilfordPress, 2009, pp. 118-147]. One such measurement involves heart ratevariability, which may be understood from the fact that both heart rateand electrodermal activity are controlled in part by neural pathwaysinvolving, for example, the anterior cingulate cortex [Hugo D.CRITCHLEY, Christopher J. Mathias, Oliver Josephs, et al. Humancingulate cortex and autonomic control: converging neuroimaging andclinical evidence. Brain 126 (2003):2139-2152; Hugo D. CRITCHLEY.Electrodermal responses: what happens in the brain. Neuroscientist 8(2,2002)132-142].

Heart rate variability is conventionally assessed by examining theFourier spectrum of successive heart rate intervals that are extractedfrom an electrocardiogram (RR-intervals). Typically, a high-frequencyrespiratory component (0.15 to 0.4 Hz, centered around about 0.25 Hz,and varying with respiration) and a slower, low frequency component(from about 0.04 to 0.13 Hz) due primarily to baroreceptor-mediatedregulation of blood pressure related to Mayer waves, are found in thepower spectrum of the heart rate. Even slower rhythms (<0.04 Hz),thought to reflect temperature, blood volume, renin-angiotensinregulation, as well as circadian rhythms, may also be present. The highfrequency respiratory component is primarily mediated by vagal activity,and consequently, high frequency spectral power is often used as anindex of cardiac parasympathetic tone. Low-frequency power can be avalid indicator of cardiac sympathetic activity under certainconditions, with the understanding that baroreceptor regulation of bloodpressure can be achieved through both sympathetic and parasympatheticpathways. However, more elaborate indices of sympathetic andparasympathetic activity may also be extracted from the variation insuccessive heart rate intervals [U. Rajendra ACHARYA, K. Paul Joseph, N.Kannathal, Choo Min Lim and Jasjit S. Suri. Heart rate variability: areview. Medical and Biological Engineering and Computing 44(12, 2006),1031-1051]. Considering that neither electrodermal nor heart ratevariability indices of sympathetic activity unambiguously characterizesympathetic activity within the central nervous system, it is preferredthat they both be measured. In fact, additional noninvasive measures ofsympathetic activity, such as variability of QT intervals, arepreferably measured as well [BOETTGER S, Puta C, Yeragani V K, Donath L,Muller H J, Gabriel H H, Bar K J. Heart rate variability, QTvariability, and electrodermal activity during exercise. Med Sci SportsExerc 42(3, 2010):443-448].

Most investigations concerning the effect of vagus nerve stimulation onheart rate variability are concerned with long-term effect on particularcategories of patients, rather than on acute effects [e.g., RONKAINEN E,Korpelainen J T, Heikkinen E, Myllyla V V, Huikuri H V, Isojarvi J I.Cardiac autonomic control in patients with refractory epilepsy beforeand during vagus nerve stimulation treatment: a one-year follow-upstudy. Epilepsia 47(3, 2006):556-562; JANSEN K, Vandeput S, Milosevic M,Ceulemans B, Van Huffel S, Brown L, Penders J, Lagae L. Autonomiceffects of refractory epilepsy on heart rate variability in children:influence of intermittent vagus nerve stimulation. Dev Med Child Neurol53(12, 2011):1143-1149]. Nevertheless, there have been severalinvestigations concerning the acute effects of vagus nerve stimulationon heart rate variability, which demonstrate that heart rate variabilitycould be used as an index of whether the vagus nerve is in fact beingstimulated. Most such studies demonstrate unambiguous heart ratevariability effects [KAMATH M V, Upton A R, Talalla A, Fallen E L.Effect of vagal nerve electrostimulation on the power spectrum of heartrate variability in man. Pacing Clin Electrophysiol 15(2, 1992):235-243;FREI M G, Osorio I. Left vagus nerve stimulation with theneurocybernetic prosthesis has complex effects on heart rate and on itsvariability in humans. Epilepsia 42(8, 2001):1007-1016; STEMPER B,Devinsky O, Haendl T, Welsch G, Hilz M J. Effects of vagus nervestimulation on cardiovascular regulation in patients with epilepsy. ActaNeurol Scand 117(4, 2008):231-236]. However, some investigators havealso reported that vagus nerve stimulation has no effect on heart ratevariability, which FREI et al attributed to methodological issues [SETTYA B, Vaughn B V, Quint S R, Robertson K R, Messenheimer J A. Heartperiod variability during vagal nerve stimulation. Seizure 7(3,1998):213-217].

The diameter of the pupil of the eye is controlled by the autonomicnervous system [John L. BARBUR Learning from the pupil—studies of basicmechanisms and clinical applications. In: L. M. Chalupa and J. S.Werner, Eds. The Visual Neurosciences. Cambridge, Mass.: MIT Press,2004, Vol. 1, pp. 641-656]. It may cause pupil dilation or constrictionnot only in response to variations in ambient light, but also inresponse to other situations, such as an increased level of arousal oralertness. Electrical stimulation of the vagus nerve by itself may causethe pupil to dilate through inhibition of parasympathetic outflow[BIANCA R, Komisaruk B R. Pupil dilatation in response to vagal afferentelectrical stimulation is mediated by inhibition of parasympatheticoutflow in the rat. Brain Res 1177 (2007):29-36]. However, normalindividuals are reported not to have unusual pupil responses, at leastto one form of vagus nerve stimulation [Daniela HUBER, AndreaFischenich, Nadine Wolf, and Jens Ellrich. Transcutaneous vagus nervestimulation has no impact on the pupillary light reflex in healthyvolunteers. Annual Meeting of the Society for Neuroscience, Neuroscience2012, 13-17 Oct. 2012, New Orleans, La., USA. Society for Neuroscience,2012. p. No. 657.11/04].

Nevertheless, patients with autonomic dysfunction are often reported ashaving abnormal pupil responses, and they are likely to be candidatesfor treatment with vagus nerve stimulation. In particular, patients withmigraine, who may also have autonomic dysfunction, are also reported tohave pupil response abnormalities, particularly with regard todifferences between left and right eyes. Furthermore, the pupils ofheadache-free migraineurs dilate after a topical application of 1%phenylephrine, whereas this low concentration has at most a minor effecton the pupil diameters of normal individuals [HARLE D E, Wolffsohn J S,Evans B J. The pupillary light reflex in migraine. Ophthalmic PhysiolOpt 25(3, 2005):240-245; PEROUTKA S J. Migraine: a chronic sympatheticnervous system disorder. Headache 44(1, 2004):53-64; HORD E D, Evans MS, Mueed S, Adamolekun B, Naritoku D K. The effect of vagus nervestimulation on migraines. J Pain 4(9, 2003):530-534; BREMNER F D, SmithS E. Pupil abnormalities in selected autonomic neuropathies. JNeuroophthalmol 26(3, 2006):209-219; MOSEK A, Novak V, Opfer-Gehrking TL, Swanson J W, Low P A. Autonomic dysfunction in migraineurs. Headache39(2, 1999)108-117]. Even in individuals who do not exhibit initialleft-right eye functional asymmetries, such asymmetry may be induced byforcing the individual to breathe only through the left or through theright nostril [BACKON J, Matamoros N, Ramirez M, Sanchez R M, Ferrer J,Brown A, Ticho U. A functional vagotomy induced by unilateral forcedright nostril breathing decreases intraocular pressure in open andclosed angle glaucoma. Br J Ophthalmol 74(10, 1990):607-609].

Therefore, pupil response in left versus right eyes (e.g., diameter andlatency), as a function of left versus right vagus nerve stimulationamplitude and other parameters, left versus right nostril breathing, asa function of ambient light, and as a function of combinations of these,may distinguish whether the left or right vagus nerve is beingstimulated at a particular stimulation amplitude. Experimentally, thepupil diameter measurements are preferably performed using infraredcameras, as described by HARLE et al., so as to be able to perform themeasurements when the ambient lighting is very low. For example, viewingan infrared image of the pupil can be accomplished with a conventionaldigital camera after removing the camera's IR-blocking filter andplacing a gel filter that blocks visible light in front of the lens.Variations in the pupil measurement procedures, for example thosedescribed by BARBUR involving flicker, spatially structured patterns,coherent motion, multi-colored stimuli, situations involving differentlevels of patient wakefulness, alertness or attention, and transcornealdrug interventions may also be performed in an attempt to find the mostsensitive pupillometric test for determining whether a vagus nerve isbeing electrically stimulated in any particular individual.

The choroid is the vascular layer of the eye, lying between the retinaand the sclera. Almost the entire blood supply of the eye comes from thechoroidal vessels, which originate from the ophthalmic arteries. Theleft and right ophthalmic arteries arise as the first major branch ofthe internal carotid artery. The choroid is vascularized by two separatearterial systems: the short posterior ciliary arteries, which supply theposterior choroid; and the long posterior ciliary arteries, which supplythe anterior portion of the choroid, as well as the iris and ciliarybody. [B. ANAND-APTE and J. G. Hollyfield. Developmental Anatomy of theRetinal and Choroidal Vasculature In: Joseph C. Besharse, Dean Bok eds.The Retina and Its Disorders, 2011 San Diego, Calif.: Academic Press,pp. 179-185].

The choroid contains dense sympathetic innervation originating in theipsilateral superior cervical ganglion. Stimulation of the cervicalsympathetic trunk, which provides preganglionic innervation to thesuperior cervical ganglion, diminishes choroidal blood flow. The choroidalso receives parasympathetic innervation from the ipsilateralpterygopalatine ganglion, which is vasodilatory. Therefore, the choroidcontains sympathetic vasoconstrictor and parasympathetic vasodilatornerves whose activity and interactions determine the level of choroidalperfusion. The sympathetic control is exercised throughout the choroid,and parasympathetic control is more selectively localized [STEINLE J J,Krizsan-Agbas D, Smith P G. Regional regulation of choroidal blood flowby autonomic innervation in the rat. Am J Physiol Regul lntegr CompPhysiol 279(1, 2000):R202-209; BILL A, Sperber G O. Control of retinaland choroidal blood flow. Eye (Lond) 4 (Pt. 2, 1990):319-325]

Choroidal blood flow responds to interventions that cause readjustmentof the autonomic nervous system, such as a change of posture, in orderto maintain a reflex constancy of perfusion to the eye and also tomaintain a constant retinal temperature [KHAYI H, Pepin J L, Geiser M H,Tonini M, Tamisier R, Renard E, Baguet J P, Levy P, Romanet J P, ChiquetC. Choroidal blood flow regulation after posture change or isometricexercise in men with obstructive sleep apnea syndrome. Invest OphthalmolVis Sci 52(13, 2011):9489-9496]. According to the present invention,when the vagus nerve is stimulated, there will also be such areadjustment of the sympathetic and parasympathetic branches of theautonomic nervous system, such that the stimulation will be accompaniedby a change in choroidal blood flow. Measurement of that flow may beperformed using devices known in the art. For example, KHAYI et al use alaser Doppler method and a confocal optical system with indirectdetection of the Doppler shifted light. The instrument uses a coherentnear-infrared probing beam (785 nm, 90 microwatt at the cornea). Thebeam is focused at the fovea, and the subject is asked to look directlyat the beam. Light back-scattered by the tissue in the sampled volume iscollected by a bundle of optic fibers and guided to an avalanchephotodiode, the photo-current from which is used to calculate choroidalblood flow [RIVA C E, Geiser M, Petrig B L. Ocular blood flow assessmentusing continuous laser Doppler flowmetry. Acta Ophthalmol 88(6,2010):622-629; POLSKA E, Polak K, Luksch A, Fuchsjager-Mayrl G,Petternel V, Findl O, Schmetterer L. Twelve hour reproducibility ofchoroidal blood flow parameters in healthy subjects. Br J Ophthalmol88(4, 2004):533-537]. For the pupil diameter and ocular blood flowmeasurement, the data may be considered separately for each eye, orindices of asymmetry may be calculated as described above in connectionwith the laryngeal electromyographic data. These data, along withelectrodermal and/or heart rate variability data may be presented to thesame support vector machine that is used to in connection with thelaryngeal data when all such data are collected simultaneously, orotherwise they may be presented to a separate support vector machine fortraining and prediction of whether a vagus nerve is being stimulated.

During and after vagus nerve stimulation, changes in blood flow near thesurface of the skin may also be measured with laser Doppler flow meters.Changes found in most of the skin surface usually reflect changes insympathetic tone (e.g., blushing or pallor of the face) that isindirectly modulated by the vagus nerve stimulation and may best bemonitored by spectral analysis in conjunction with heart rate andrespiration variability analysis [SODERSTROM T, Stefanovska A, Veber M,Svensson H. Involvement of sympathetic nerve activity in skin blood flowoscillations in humans. Am J Physiol Heart Circ Physiol 284(5,2003):H1638-46 BERNARDI L, Rossi M, Fratino P, Finardi G, Mevio E,Orlandi C. Relationship between phasic changes in human skin blood flowand autonomic tone. Microvasc Res 37(1, 1989)16-27]. However, changes ofblood flow to specialized surfaces such as the nasal mucosa, lips,mouth, palms of the hand and outer ear canal may have control thatreflects additional control by parasympathetic as well as sympatheticarms of the autonomic nervous system. Consequently, changes in bloodflow there may be better suited to the inference that vagus nervestimulation has occurred [MEVIO E, Bernardi L. Phasic changes in humannasal and skin blood flow: relationship with autonomic tone. Ann OtolRhinol Laryngol 103(10, 1994):789-795; IZUMI H, Karita K. Reflexvasodilatation in the cat lip evoked by stimulation of vagal afferents.J Auton Nery Syst 42(3.1993):215-223]. For paired structures such as thenostrils, differences between flow in the contralateral and ipsilateralsides, relative to the site of vagus nerve stimulation, may also give anindication of whether a vagus nerve has been stimulated.

Although the electrodermal and heart rate variability measurements,along with pupil diameter and blood flow measurements, provide thepreferred data concerning autonomic effects demonstrating vagus nervestimulation, many other autonomic tests may be performed to providecomplementary or confirmatory information. It should be noted that theremay be significant variation between individuals with regard to evokedautonomic reflexes, and a battery of tests may be useful for thoseindividuals in whom the preferred measurements give equivocal results.

First, consideration may be given to the genetic information about theindividual if it is available. Patients at large are known to beparticularly polymorphic with respect to their beta-2-adrenergicreceptors, which cause significant variation in blood pressure control,vascular responses, and the responses to interventions in diseases suchas asthma. Such polymorphism data may be available for an individual inconnection with predicting his or her responses to drugs that modulatethe autonomic nervous system, some of which may also be used as part ofthe battery of autonomic tests that are described below [Shelli L.KIRSTEIN and Paul A. Insel. Autonomic nervous system pharmacogenomics: aprogress report. Pharmacological Reviews 56(1, 2004):31-52]. Similarly,if the patient is being treated with vagus nerve stimulation formigraine headaches, variable responsiveness among individuals to thestimulation may be attributable in part to genetic factors. Relevantgenetic contributions may have already been ascertained in connectionwith evaluating responsiveness to drugs that the patient has or willreceive as previous or concurrent treatment, or at least geneticcontributions may be inferred from the fact that the patient respondsbetter to some drugs than others [Maria PAINE, Patrizia Lulli, IvanoFarinelli, Simona Simeoni, Sergio De Filippis, Francesca RomanaPatacchioli, and Paolo Martelletti. Genetics of migraine andpharmacogenomics: some considerations. J Headache Pain 8(6, 2007):334-339].

Second, patients treated with vagus nerve stimulation who suffer frommigraine headaches and other disorders may already be known to exhibitautonomic dysfunction [C. MATHIAS. Autonomic diseases: clinical featuresand laboratory evaluation. J Neurol Neurosurg Psychiatry 74(Suppl 3,2003): iii31-iii41]. Standard tests that may have been used to evaluatetheir autonomic function also show considerable inter-patientvariability, such that a battery of tests is needed to evaluateautonomic status. The tests ordinarily include the analysis of heartrate variability, as described above. A more complete heart ratevariability test is provided by simultaneously measuring heart rate andblood pressure (e.g., with a wrist tonometer), in which beat-to-beatfluctuations in heart rate and blood pressure are correlated. In anothercommon test, the sympathetic skin response test to measure sudomotorfunction, the patient is subjected to an unexpected stimulus, such aselectrical stimulation of the ulnar nerve at the elbow (or in thepresent application, the vagus nerve), a request for rapid and deepinspiration, a loud noise (hands clapped unexpectedly), or touching tothe body unexpectedly. Galvanic skin response is then recorded. Thus, inthe present invention, the preferred tests for demonstrating stimulationof the vagus nerve include two tests that are often performed byneurologists when they assess autonomic function in a patient, namelyheart rate variability and sympathetic skin response.

Additional autonomic tests that may be performed before, during, andafter vagus nerve stimulation are as follows. A valsalva maneuverevaluates the baroreflex arc, in which the patient breathes into aspecial mouthpiece and maintains an expiratory pressure of 40 mg for 15to 20 seconds. Heart rate (and optionally beat-to-beat blood pressure,e.g., with a wrist tonometric device) is monitored, and their timecourse gives an indication of sympathetic and parasympathetic function.Deep metronomic breathing testing at 6 breaths per minute assessesrespiratory sinus arrhythmia through an analysis of the correspondingheart rate.

In the sustained handgrip test to test sympathetic activity, the patientpresses a handgrip dynamometer at full strength, and then maintains agrip for 3 to 5 minutes at one-third of the maximum. The time course ofheart rate and beat-to-beat blood pressure gives an indication of earlyvagal withdrawal followed by sympathetic activation. In the cold pressortest, e.g., to evaluate sympathetic efferent nerves, one hand and armare placed in ice water for 40 to 180 seconds. Heart rate, bloodpressure, and peripheral blood flow (by laser Doppler flowmetry) aremeasured. In the cold face test, cold compresses (1.degree. C. to2.degree. C.) are applied to the forehead and maxillary region of thesubject's face for a period of 1 to 3 minutes. Heart rate andbeat-to-beat blood pressure responses are then measured, such that adisturbance in the trigeminal-brainstem-vagal reflex arc would producean abnormal response.

In orthostatic challenge maneuvers, the patient is initially in arecumbent position, and then assumes an upright position, either byactively standing or by being passively rotated to typically 60 or 70degrees on a table that tilts. The responses in heart rate and bloodpressure responses are then monitored. In a mental arithmetic test, thepatient is asked to count backwards from 100 subtracting 7 or 13 eachtime, and changes in systolic blood pressure are recorded.

In pharmacological baroreflex testing, pressor or depressor drugs areinfused to increase or decrease the blood pressure, and the heart rateand blood pressure responses are monitored. In neck chamber baroreflextesting, positive or negative pressure is applied to a collar around theneck. The heart rate and blood pressure responses are then recorded. Ina lower body negative pressure test, a similar device is applied to thelower portion of the patient's body.

In a thermoregulatory sweat test, the patient is placed in a chamber inwhich humidity (35-40%) and temperature (45-50 degrees C.) areregulated. Body areas having abnormal sweating patterns are thendocumented, from which it is inferred that certain axons may befunctioning abnormally. In the quantitative sudomotor axon reflex test(QSART) to measure the autonomic nerves that control sweating,electrical stimulation on the skin (iontophoresis), allows acetylcholineto stimulate sweat glands. The QSART measures the volume of sweatproduced by this stimulation [Safwan S. JARADEH, Thomas E. Prieto.Evaluation of the autonomic nervous system. Phys Med Rehabil Clin N Am14 (2003) 287-305; HILZ M J, Dutsch M. Quantitative studies of autonomicfunction. Muscle Nerve 33(1, 2006):6-20; Agnieszka ZYGMUNT and JerzyStanczyk. Methods of evaluation of autonomic nervous system function.Arch Med Sci 6(1, 2010): 11-18; Heinz LAHRMANN, Isabel Rocha, WalterStruhal, Roland D Thijs, and Max Hilz. Diagnosing Autonomic NervousSystem Disorders-Existing Guidelines and Future Perspectives. EuropeanNeurological Review 6(1, 2011):52-56; H TANAKA and H Tamai. Recentadvances in autonomic function tests of the cardiovascular system inchildren. Medical Principles and Practice 7 (1998):157-171; ILLIGENS BM, Gibbons C H. Sweat testing to evaluate autonomic function. Clin AutonRes 19 (2, 2009):79-87; KUCERA P, Goldenberg Z, Kurca E. Sympatheticskin response: review of the method and its clinical use. Bratisl LekListy 105(3, 2004)108-116]. WEIMER gives a more complete list ofautonomic tests, noting that pupillometry is considered to beinvestigational [WEIMER L H. Autonomic testing: common techniques andclinical applications. Neurologist 16(4, 2010):215-222].

The most detailed investigations of blood flow changes following vagusnerve stimulation have dealt with flow changes within the brain itself.Transcranial Doppler flow meters have been used unsuccessfully in anattempt to measure changes in cerebral blood flow [NEU P, Heuser I,Bajbouj M. Cerebral blood flow during vagus nerve stimulation—atranscranial Doppler study. Neuropsychobiology 51(4, 2005):265-268].However, three imaging methods have demonstrated changes in cerebralblood flow after vagus nerve stimulation, namely: positron emissiontomography (e.g., PET with oxygen-15 labeled water), functional magneticresonance imaging (fMRI), and single-photon emission computed tomography(SPECT, e.g. with 99 mTc-ethyl cysteinate dimer).

Examples of PET imaging during vagus nerve stimulation are given byHENRY et al and by CONWAY et al [HENRY T R, Votaw J R, Pennell P B,Epstein C M, Bakay R A, Faber T L, Grafton S T, Hoffman J M. Acute bloodflow changes and efficacy of vagus nerve stimulation in partialepilepsy. Neurology 52(6, 1999):1166-1173; CONWAY C R, Sheline Y I,Chibnall J T, George M S, Fletcher J W, Mintun M A. Cerebral blood flowchanges during vagus nerve stimulation for depression. Psychiatry Res.146(2, 2006)179-184].

Examples of fMRI imaging during vagus nerve stimulation are given byNARAYANAN et al, LIU et al, and KRAUS et al [NARAYANAN J T, Watts R,Haddad N, Labar D R, Li P M, Filippi C G. Cerebral activation duringvagus nerve stimulation: A functional MR study. Epilepsia. 43(2002):1509-1514; W-C LIU, K Mosier, A J Kalnin, D Marks. BOLD fMRIactivation induced by vagus nerve stimulation in seizure patients. JNeurol Neurosurg Psychiatry 74 (2003):811-813; KRAUS T, Hosl K, Kiess O,Schanze A, Kornhuber J, Forster C. BOLD fMRI deactivation of limbic andtemporal brain structures and mood enhancing effect by transcutaneousvagus nerve stimulation. J Neural Transm 114(11, 2007)1485-1493].

An example of SPECT imaging during vagus nerve stimulation is given byVAN LAERE et al [VAN LAERE K, Vonck K, Boon P, Brans B, VandekerckhoveT, Dierckx R. Vagus nerve stimulation in refractory epilepsy: SPECTactivation study. J Nucl Med 41(7, 2000)1145-1154]. The objective ofthese investigations was to determine which brain structures areactivated or deactivated during vagus nerve stimulation. However, in thepresent context, the finding that there are any differences in cerebralblood flow as the result of vagus nerve stimulation would constituteevidence that the vagus nerve was in fact stimulated. The differentimaging studies were reviewed by CHAE et al. and by BARI et al., whichindicate that imaging by these methods often gives inconsistent and evencontradictory results regarding the particular brain structures that areactivated [CHAE J H, Nahas Z, Lomarev M, Denslow S, Lorberbaum J P,Bohning D E, George M S. A review of functional neuroimaging studies ofvagus nerve stimulation (VNS). J Psychiatry Res. 37(6, 2003):443-55;Ausaf A. BARI and Nader Pouratian. Brain imaging correlates ofperipheral nerve stimulation. Surg Neurol Int 3(Suppl 4, 2012):S260-S268].

Additional tests of whether the vagus nerve is being stimulated mayinvolve the measurement of evoked potentials, as now described. Anevoked potential or evoked response is an electrical potential recordedfrom the nervous system following presentation of a stimulus, asdistinct from spontaneous potentials detected by electroencephalography(EEG) or other electrophysiological recording methods. Usually the term“evoked potential” is reserved for responses involving either recordingfrom, or stimulation of, central nervous system structures. An“event-related potential” is the measured brain response that is thedirect result of a specific sensory, cognitive, or motor event. Thestimulus event in the present context is vagus nerve stimulation, butother stimuli may also be presented to the patient (e.g., visual orauditory). Event-related potentials are measured withelectroencephalography (EEG) or more generally with scalp sensors CASSONA, Yates D, Smith S, Duncan J, Rodriguez-Villegas E. Wearableelectroencephalography. What is it, why is it needed, and what does itentail? IEEE Eng Med Biol Mag. 29(3, 2010):44-56; ATSUMORI H, Kiguchi M,Obata A, Sato H, Katura T, Funane T, Maki A. Development of wearableoptical topography system for mapping the prefrontal cortex activation.Rev Sci Instrum. 2009 April; 80(4):043704, pp. 1-6]. Signal processingmethods, comprising not only the application of conventional linearfilters to the raw EEG data, but also the nearly real-time extraction ofnon-linear signal features from the data, may be considered to be a partof the EEG recording [D. Puthankattil SUBHA, Paul K. Joseph, RajendraAcharya U, and Choo Min Lim. EEG signal analysis: A survey. J Med Syst34 (2010)195-212]. The magnetoencephalography (MEG) equivalent ofevent-related potential is the event-related field.

The effects of vagus nerve stimulation on surface EEG waveforms may bedifficult to detect [Michael BEWERNITZ, Georges Ghacibeh, Onur Seref,Panos M. Pardalos, Chang-Chia Liu, and Basim Uthman. Quantification ofthe impact of vagus nerve stimulation parameters onelectroencephalographic measures. AIP Conf. Proc. DATA MINING, SYSTEMSANALYSIS AND OPTIMIZATION IN BIOMEDICINE; Nov. 5, 2007, Volume 953, pp.206-219; Michael Andrew BEWERNITZ. Data mining and time series analysisof brain dynamical behavior with applications in epilepsy. PhD.Dissertation. Gainesville, Fla.: University of Florida. 2008. pp:1-246]. However, they may exist nevertheless [KOO B. EEG changes withvagus nerve stimulation. J Clin Neurophysiol. 18(5, 2001):434-41; KUBAR, Guzaninova M, Brazdil M, Novak Z, Chrastina J, Rektor I. Effect ofvagal nerve stimulation on interictal epileptiform discharges: a scalpEEG study. Epilepsia. 43(10, 2002):1181-8; RIZZO P, Beelke M, De CarliF, Canovaro P, Nobili L, Robert A, Formaro P, Tanganelli P, Regesta G,Ferrillo F. Modifications of sleep EEG induced by chronic vagus nervestimulation in patients affected by refractory epilepsy. ClinNeurophysiol. 115(3, 2004):658-64]. By including the analysis of ECGdata with EEG data, the diagnostic value of the EEG may be improved [M.VALDERRAMA, S. Nikolopoulos, C. Adam, Vincent Navarro and M. Le VanQuyen. Patient-specific seizure prediction using a multi-feature andmulti-modal EEG-ECG classification. XII Mediterranean Conference onMedical and Biological Engineering and Computing 2010, IFMBEProceedings, 2010, Volume 29, Part 1, 77-80]. In addition, the use of awavelet transform of the EEG data may enable the detection of effects ondifferent spectral components [Zhaoyang CHEN, Hongwei Hao, Luming Li,Jie Dong. Wavelet Transform for Rabbit EEG with Vagus Nerve ElectricStimulation. Proceedings of the 28th IEEE EMBS Annual InternationalConference New York City, USA, Aug. 30-Sep. 3, 2006 pp. 1715-1718].

HENRY reviewed the effects of vagus nerve stimulation on evokedpotentials and noted that investigators have obtained contradictoryresults [HENRY TR. Therapeutic mechanisms of vagus nerve stimulation.Neurology 59(6 Suppl 4, 2002):53-514]. BRAZDIL found that vagus nervestimulation has no effect on auditory evoked potentials but found someeffect on visual evoked potentials [BRAZDIL M, Chadim P, Daniel P, KubaR, Rektor I, Novak Z, Chrastina J. Effect of vagal nerve stimulation onauditory and visual event-related potentials. Eur J Neurol 8(5,2001):457-461]. CONTE et al found that for patients undergoing vagusnerve stimulation, Fourier analysis of responses to stimuli identifiesalterations in visual evoked potentials that are not found with standardanalysis of latencies and amplitude response [Mary M. CONTE and JonathanD. Victor. VEP indices of cortical lateral interactions in epilepsytreatment. Vision Res 49(9, 2009): 898-906]. POLAK and colleagues foundthat auricular vagus nerve stimulation resulted in somatosensory-evokedpotentials that were characterized by significantly longer latencies ascompared to controls [POLAK T, Ehlis A C, Langer J B, Plichta M M,Metzger F, Ringel T M, Fallgatter A J. Non-invasive measurement of vagusactivity in the brainstem—a methodological progress towards earlierdiagnosis of dementias? J Neural Transm. 2007; 114(5, 2007):613-619;POLAK T, Markulin F, Ehlis A C, Langer J B, Ringel T M, Fallgatter A J.Far field potentials from brain stem after transcutaneous vagus nervestimulation: optimization of stimulation and recording parameters. JNeural Transm 116(10, 2009):1237-1242]. USAMI et al found that evokedpotentials from vagus nerve stimulation are most likely generated byvagal afferents at the jugular foramen near the entrance to the cranium,but some components are due to excitation of laryngeal muscles [USAMI K,Kawai K, Sonoo M, Saito N. Scalp-recorded evoked potentials as a markerfor afferent nerve impulse in clinical vagus nerve stimulation. BrainStimul. 2012 Oct. 11. pii: 51935-861X(12)00161-1, pp. 1-9].

Reported effects of vagus nerve stimulation on physiological variablesmeasured as vital signs have been contradictory, such as effects onabsolute heart rate (as opposed to heart rate variability), respiratoryfrequency, and blood pressure. Differences in the reported effects mostlikely reflect differences in which nerve fibers are stimulated, whichare a function of the amplitude and other parameters of the vagus nervestimulation. For example, BINKS et al reported that vagus nervestimulation has no cardiorespiratory effects, provided that no C fibersare stimulated [BINKS A P, Paydarfar D, Schachter S C, Guz A, Banzett RB. High strength stimulation of the vagus nerve in awake humans: a lackof cardiorespiratory effects. Respir Physiol 127(2-3, 2001):125-133]. Onthe other hand, ZAAIMI et al reported that vagus nerve stimulation has apronounced effect on respiration; HASHIBA reported that vagus nervestimulation can induce bradycardia and bronchoconstriction if C fibersare activated; YOO et al reported that vagus nerve stimulation caninduce bradycardia; FREI et al reported complex effects such asbradycardia followed by tachycardia; PLACHTA et al demonstrated that itis possible to use vagus nerve stimulation to modulate blood pressurewithout changing heart rate or respiration rate [ZAAIMI B, Heberle C,Berquin P, Pruvost M, Grebe R, Wallois F. Vagus nerve stimulationinduces concomitant respiratory alterations and a decrease in SaO2 inchildren. Epilepsia. 2005 November; 46(11, 2005):1802-1809; HASHIBA E,Hirota K, Suzuki K, Matsuki A. Effects of propofol onbronchoconstriction and bradycardia induced by vagal nerve stimulation.Acta Anaesthesiol Scand. 2003 October; 47(9, 2003):1059-1063; YOO P B,Hincapie J G, Hamann J J, Ruble S B, Wolf P D, Grill W M. Selectivecontrol of physiological responses by temporally-patterned electricalstimulation of the canine vagus nerve. Conf Proc IEEE Eng Med Biol Soc.2011; 2011:3107-3110; FREI MG, Osorio I. Left vagus nerve stimulationwith the neurocybernetic prosthesis has complex effects on heart rateand on its variability in humans. Epilepsia 42(8, 2001):1007-1016;Dennis T. T. PLACHTA, Oscar Cota, Nayeli Espinosa, Thomas Stieglitz, andMortimer Gierthmuehlen. Selective stimulation of the vagus nervecontrols the blood pressure and simultaneously avoids significant sideeffects of bradycardia and bradypnea. Proceedings of TechnicallyAssisted Rehabilitation (TAR 2013), 4th European Conference, Mar. 14-15,2013 in Berlin, Session 9, Event 2: pp. 1-4]. This is to say thatchanges in vital signs that accompany vagus nerve stimulation may serveto demonstrate that the nerve is being stimulated, but also that theparameters of the stimulation may not be optimal if such side effectsoccur.

Other tests for whether the vagus nerve is being stimulated includechanges in pain threshold, changes in balance or sway, and changes inthe chemistry of blood or other bodily fluids. NESS et al found thatvagus nerve stimulation produces a change in the threshold for pain,which was measured by a thermode applied to the skin of the forearm[NESS T J, Fillingim R B, Randich A, Backensto E M, Faught E. Lowintensity vagal nerve stimulation lowers human thermal pain thresholds.Pain 86(1-2, 2000):81-85]. CLARKE et al found that vagus nervestimulation has no significant effects on bodily sway with eyes open andclosed, although limitations to the study were noted by theinvestigators [CLARKE B M, Upton A R, Kamath M, Griffin H M.Electrostimulation effects of the vagus nerve on balance in epilepsy.Pacing Clin Electrophysiol 15(10 Pt 2, 1992):1614-1630]. For patientswho experience tremor or gait problems, comparing balance tests beforeand after vagus nerve stimulation, as well as electromyography duringeffort and standard tests of gait (e.g., Rhomberg test), may be used todemonstrate that the vagus nerve is being simulated.

Vagus nerve stimulation does not cause significant changes in hematologyor common blood chemistry values over an extended period of time, butacute changes have apparently not been investigated [SCHACHTER S C,Saper C B. Vagus nerve stimulation. Epilepsia 39(7, 1998):677-686;HANDFORTH A, DeGiorgio C M, Schachter S C, et al. Vagus nervestimulation therapy for partial-onset seizures: a randomizedactive-control trial. Neurology 51(1, 1998):48-55]. A general bloodmarker of vagus nerve stimulation is the circulating level of TNF-alphacompared before/after stimulation. Alternatively, cytokines such asIL-1B, IL-6, IL-8 and IL-10 or other markers for inflammation may beused as a biomarker for vagus nerve stimulation [CORCORAN C, Connor T J,O'Keane V, Garland MR. The effects of vagus nerve stimulation on pro-and anti-inflammatory cytokines in humans: a preliminary report.Neuroimmunomodulation 12(5, 2005):307-309; SLOAN R P, McCreath H, TraceyK J, Sidney S, Liu K, Seeman T. RR interval variability is inverselyrelated to inflammatory markers: the CARDIA study. Mol Med 13(3-4,2007)178-184].

One may also use other blood-borne chemicals as biomarkers for vagusnerve stimulation, especially if they are relevant to the disease beingtreated. For example, circulating serotonin has many cardiovasculareffects that might be useful therapeutically or that may cause sideeffects. Release of serotonin from the enterochromaffin cells of the gutis regulated by the vagus nerve, and its release into the portalcirculation is controlled by vagal efferent adrenergic nerve fibers[GRONSTAD K O, Zinner M J, Nilsson O, Dahlstrom A, Jaffe B M, Ahlman H.Vagal release of serotonin into gut lumen and portal circulation viaseparate control mechanisms. J Surg Res 44(2, 1988):146-151; PETTERSSONG. The neural control of the serotonin content in mammalianenterochromaffin cells. Acta Physiol Scand Suppl 470 (1979):1-30].Another example is the blood level of gastrin in a fasting individual,before versus after vagus nerve stimulation [H. T. DEBAS and S. H.Carvajal. Vagal regulation of acid secretion and gastrin release. Yale JBiol Med 67(3-4, 1994): 145-151]. Another example is the circulatinglevel of noradrenaline in the supine versus standing positions.

Studies on the long-term effect of vagus nerve stimulation on thecomposition of cerebrospinal fluid (CSF) have also been performed, butapparently no studies concerning acute stimulation effects have beenperformed [HENRY TR. Therapeutic mechanisms of vagus nerve stimulation.Neurology 59(6 Suppl 4, 2002):53-514]. Considering that collecting suchacute data would involve performing a lumbar puncture, it would bedifficult to justify using CSF composition as a biomarker for acutevagus stimulation. The chemical composition of urine (e.g.,noradrenaline level), sweat, and/or saliva may also show slight changesfollowing vagus nerve stimulation, but a greater effect of thestimulation is likely to be on the volume of their production, throughmechanisms involving the autonomic nervous system, tests for which weredescribed in previous paragraphs.

Vagus Nerve Self-Stimulation by the Patient

When a patient is using the stimulation device to performself-stimulation therapy, e.g., at home or at a workplace, he or shewill follow the steps that are now described. In the followingdescription, it is assumed that the stimulator (30 in FIG. 3) has beenplaced in a docking station (40 in FIG. 3), where it would ordinarily beplaced between stimulation sessions for protection and safekeeping. Theprevious stimulation session will ordinarily have discharged therechargeable batteries of the stimulator housing, and between sessions,the docking station will have recharged the stimulator at most only upto a minimum level. If the stimulator's batteries had charge remainingfrom the previous stimulation session, the docking station will havedischarged the stimulator to a minimum level that will not supportstimulation of the patient.

The patient will then interact with the mated docking station andstimulator via one of the handheld or internet-based devices (333 inFIG. 5), to which the docking station can be connected wirelessly orthrough a cable. For example, the patient can initiate the stimulationsession using a mobile phone (FIG. 4B) or laptop computer (FIG. 4D) byinvoking a computer program (on the laptop computer or through an app onthe mobile phone) that is designed to initiate use of the stimulator.For security reasons, the program would begin with the request for auser name and a password, and that user's demographic information andany data from previous stimulator experiences would already beassociated with it in the login account. If the patient's physician hasnot authorized further treatments, the docking station will not chargethe stimulator's batteries, and instead, the computer program will callor otherwise communicate with the physician's computer requestingauthorization. After authorization by the physician is received, thecomputer program (on the laptop computer or through an app on the mobilephone) may also query a database that is ordinarily located somewhere onthe internet to verify that the patient's account is in order. If it isnot in order, the program may then request prepayment for one or morestimulation sessions, which would be paid by the patient using a creditcard, debit card, PayPal or the like. The computer program will alsoquery its internal database or that of the docking station to determinethat sufficient time has elapsed between when the stimulator was lastplaced in the docking station and the present time, to verify that anyrequired wait-time has elapsed.

Having received authorization to perform a nerve stimulation session,the patient interface computer program will then ask the patientquestions that are relevant to the selection of parameters that thedocking station will use to make the stimulator ready for thestimulation session. The questions that the computer program asks aredependent on the condition for which the patient is being treated, whichfor present purposes is considered to be treatment for a migraineheadache. That headache may in principle be in any of the headachephases (prodrome, aura, headache pain, postdrome, and interictalperiod), which would be ascertained through the computer program'squestions. The questions may be things like (1) is this an acute orprophylactic treatment? (2) if acute, then how severe is your headache,how long have you had it, (3) has anything unusual or noteworthyoccurred since the last stimulation?, etc. In general, the types ofposed questions are ones that would be placed in a headache diary[TASSORELLI C, Sances G, Allena M, Ghiotto N, Bendtsen L, Olesen J,Nappi G, Jensen R. The usefulness and applicability of a basic headachediary before first consultation: results of a pilot study conducted intwo centers. Cephalalgia 28(10, 2008):1023-1030].

After having received such preliminary information from the patient, thecomputer program will then send data to the docking station, giving itthe instructions needed to perform instrument diagnostic tests of thestimulator and docking station and to make the stimulator ready for thestimulation session. In general, the algorithm for setting thestimulator parameters will have been decided by the physician and willinclude the extent to which the stimulator batteries should be charged,which the vagus nerve should be stimulated (right or left), and the timethat the patient must wait after the stimulation session is ended untilinitiation of a subsequent stimulation session. The computer will querythe physician's computer to ascertain whether there have been anyupdates to the algorithm, and if not, will use the existing algorithm.The patient will also be advised of the stimulation session parametervalues by the interface computer program, so as to know what to expect.

Once the docking station has rapidly charged the stimulator's batteriesto the requisite charge, a light will turn on (e.g., green) on the frontof the docking station. At that point, the patient may remove thestimulator from the docking station to begin the vagus nervestimulation, as shown in FIG. 6. The present invention discloses methodsto assure that the patient places the stimulator at an optimal positionon the neck, the position having been determined previously by ahealthcare provider using ultrasound imaging and/or an evaluation of theneck location at which the vagus nerve stimulation produces an optimalphysiological response. As described above, the preferred stimulationposition on the patient's neck can be marked by the healthcare providerby inserting a dye-soaked cotton swab through “wormhole” ducts withinthe centerpiece (46 in FIG. 3A) of a stimulator. The swab enters throughan entrance port (48 in FIG. 3A) and eventually reaches the patient'sskin at an exit port (49 in FIG. 3A), where it stains the patient'sskin.

The preferred type of dye is a fluorophore that is only visible ordetectable as a spot on the patient's neck when one shines non-visiblelight upon it, e.g., ultraviolet light (“blacklight”) or infrared light.This is because the patient is thereby spared the embarrassment ofexplaining why there would otherwise be a visible spot marks on his orher neck, and also because such a dye is suitable for showing where toplace the stimulator irrespective of whether the patient is dark-skinnedor light-skinned. Another method, which is to attempt to match the colorof the dye to the patient's flesh color, would be generally impractical.Marking with a fluorescent dye (e.g., from ordinary highlighting pens)has also been performed by surgeons and radiologists to outline where aprocedure is to be performed. However, the marking in the presentinvention is different in that it is intended to be used repeatedly by apatient alone for device-positioning at small discrete spots, andfluorescence from the marked spots is actually measured here by thestimulator, rather than being simply imaged or viewed [DAVID, J. E.,Castle, S. K. B., and Mossi, K. M. Localization tattoos: an alternativemethod using fluorescent inks. Radiation Therapist 15 (2006):1-5;WATANABE M, Tsunoda A, Narita K, Kusano M, Miwa M. Colonic tattooingusing fluorescence imaging with light-emitting diode-activatedindocyanine green: a feasibility study. Surg Today 39(3, 2009):214-218].

Once the position-indicating spots have been made on the patient's skinas described above, they will fade and eventually disappear as thestained outer surface of the patient's skin exfoliates. The exfoliationwill occur naturally as the patient washes his or her neck and may beaccelerated by mechanical (e.g., abrasive) or chemical methods that areroutinely used by cosmetologists. Before the spot disappears, thepatient or a family member may reapply the dye/fluorophor to the samespot while observing it with ultraviolet or infrared light (as the casemay be), by masking the skin outside the spot and then applying new dyesolution directly with a cotton swab. Viewing of the fluorescence fromultraviolet light can be done with the naked eye, and viewing offluorescence from infrared light can be done with a conventional digitalcamera after removing the camera's IR-blocking filter. Some of theinfrared fluorescent dyes may also be faintly visible to the naked eyeeven under room light, depending on their concentration (e.g.,indocyanine green).

Alternatively, a semi-permanent or permanent tattooing method ofre-marking the spots may be used by a licensed professional tattooer, byinjecting the dye/fluorophor into an outer skin layer or deeper into theskin, respectively [Maria Luisa Perez-COTAPOS, Christa De Cuyper, andLaura Cossio. Tattooing and scarring: techniques and complications. In:Christa de Cuyper and Maria Luisa Cotapos (Eds.). DermatologicComplications with Body Art: Tattoos, Piercings and Permanent Make-Up.Berlin and London: Springer, 2009, pp. 31-32]. Many dyes can be used forthe ultraviolet marking, but the most convenient ones for skin-surfacemarking are those that are commercially available to hand-stampattendees of events. For tattooing applications, ultraviolet-absorbinginjectable fluorophores are commercially available that are encapsulatedwithin microspheres [Technical sheet for Opticz UV Blacklight ReactiveBlue Invisible Ink. 2013. Blacklight.com, 26735 W Commerce Dr Step 705,Volo, III. 60073-9658; Richard P. HAUGLAND. Fluorophores excited with UVlight. Section 1.7 In: The Molecular Probes Handbook: A Guide toFluorescent Probes and Labeling Technologies, 11th Edition, 2010.Molecular Probes/Life Technologies. 4849 Pitchford Ave., Eugene, Oreg.97402. pp. 66-73; Technical sheet for BIOMATRIX System. 2013. NEWWESTTechnologies, Santa Rosa Calif. 95407-0286].

Many dyes can also be used for the infrared marking, their majoradvantage being that autofluorescence from human skin or tissuegenerally does not interfere with detection of their fluorescence. Infact, they may be imaged two centimeters under the skin. Examples ofsuch dyes are indocyanine green and Alexa Fluor 790. Quantum dots mayalso be used to generate infrared fluorescence, advantages of which arethat they are very stable and very brightly fluorescent. They may alsobe encapsulated in microspheres for purposes of tattooing. Quantum dotsmay also be electroluminescent, such that the electric field andcurrents produced by the stimulator might alone induce the emission ofinfrared light from the quantum dots. They might be imaged even if thequantum dots were deep in the vicinity of the vagus nerve, owing to thelack of bodily autofluorescence in infrared windows. For example, ifthey were injected into the circulation, electroluminescence from thevagal artery may be imaged, provided that the electric field from thevagus nerve stimulator penetrates to that depth, and theirelectroluminescent intensity should be proportional to the amplitude ofthe stimulation electric field. Alternatively, the quantum dots may beinjected into the skin to the vicinity of the vagus nerve, whereupontheir electroluminescence would demonstrate an electric field thatpenetrated to that depth [Richard P. HAUGLAND. Alexa Fluor Dyes Spanningthe Visible and Infrared Spectrum—Section 1.3; and QdotNanocrystals—Section 6.6. In: The Molecular Probes Handbook: A Guide toFluorescent Probes and Labeling Technologies, 11th Edition, 2010.Molecular Probes/Life Technologies. 4849 Pitchford Ave., Eugene, Oreg.97402; GRAVIER J, Navarro F P, Delmas T, Mittler F, Couffin A C, VinetF, Texier I. Lipidots: competitive organic alternative to quantum dotsfor in vivo fluorescence imaging. J Biomed Opt. 16(9, 2011):096013;ROMOSER A, Ritter D, Majitha R, Meissner K E, McShane M, Sayes C M.Mitigation of quantum dot cytotoxicity by microencapsulation. PLoS One.6(7, 2011):e22079:pp. 1-7; Andrew M. SMITH, Michael C. Mancini, andShuming Nie. Second window for in vivo imaging. Nat Nanotechnol 4(11,2009): 710-711].

Once the patient is ready to apply the stimulator as shown in FIG. 6, heor she will place the stimulator at a position thought to beapproximately correct, then move it across the surface of the neck in anattempt to align positions of the apertures or windows 49 in FIG. 3Dwith the positions of the stained or tattooed spots on the his or herskin. The stimulator will sense when the alignment is correct, as shownin FIG. 3D, using a light source, dichroic mirror, filter, andphotodetector. The light source is preferably a light emitting diode(LED) with integral lens that emits light that causes the fluorescentdye/fluorophore to fluoresce. For example, if ultraviolet light causesthe dye to fluoresce blue light, the LED may be selected to emit lightin the near ultraviolet at a wavelength between 375 to 395 nm. Ifinfrared light causes the dye (e.g., indocyanine green) to fluoresce ata wavelength greater than 820 nm, the LED may be selected to emit lightat a wavelength or 760 or 785 nm. The light emitted from the LED isindicated in FIG. 3D as 51. As shown, time-varying power to the LEDcauses the light amplitude to oscillate at a frequency that isdetermined by the LED power source. For example, the frequency could bethat illustrated in FIG. 2B. The emitted light 51 then encounters adichroic mirror that mostly reflects light below a certain wavelengthand passes light having longer wavelengths. For example, if the LEDemits light in the near ultraviolet, the reflected light should also bein the near ultraviolet. Accordingly, the dichroic mirror could beselected to reflect light with a wavelength less than 410 nm and passlonger wavelengths (e.g., blue light at 450 nm). If the LED emits lightat a wavelength of 785 nm or less, the dichroic mirror could be selectedto reflect light with a wavelength less than 820 nm and pass longerwavelengths. The reflected light is shown in FIG. 3D as 52. That lightwill then pass through the aperture 49. Note that a window may have beenplaced within the aperture 49 to keep the system clean, in which casethe window will have been selected to pass all relevant wavelengths oflight and be essentially non-reflective. A small percentage of the lightemitted by the LED 51 will unavoidably pass through the dichroic mirror,which is indicated as 53 in FIG. 3D. That light is absorbed by a stop,as shown in the figure.

Once the light passes through the aperture 49, it encounters thepatient's skin. If the aperture has not been aligned with thefluorophore-containing spot on the patient's skin, the unstained skinitself may emit autofluorescence, which would be more of an issue withthe ultraviolet illumination than with the infrared illumination. Butwhen the aperture does align with the spot, the dye in the spot shouldfluoresce intensely. In either case, some of the light from the LED willalso be backscattered through the aperture, i.e., the light emergingfrom the patient's skin will be a combination of backscatter (no changeof wavelength) plus fluorescence (light having a longer wavelength thanthat from the LED). The light emanating from the patient's skin isindicated as 54 in FIG. 3D. The backscattered light within 54 will bereflected by the dichroic mirror towards the LED (55 in FIG. 3D). Theremaining light will pass through the dichroic mirror towards aphotodetector (56 in FIG. 3D). The relatively small portion of light 56that is backscatter is filtered out using a notch filter, selected toremove light having a wavelength at or near that produced by the LED.Thus, the light that impinges on the photodetector is almost entirelythe longer wavelength fluorescence, consisting of fluorescence from thedye, along with any autofluorescence emanating from the patient's skin.

The photodetector may be any detector known in the art to be responsiveto light at the fluorescence wavelengths, such as a silicon photodiode.The photodetector then converts the fluorescent light signal into eithera current or voltage signal, depending upon the mode of operation.Because the current or voltage signal will also have superimposed noise,it is filtered at the same frequency as the modulation frequency of theLED light emission, thereby removing noise that generally has frequencycontent different than the light modulation frequency. If the signal isparticularly noisy, lock-in amplifier (phase-sensitive detector) methodsmay also be used to extract the amplitude of the fluorescence signal.When the aperture (49 in FIG. 3D) is eventually aligned with the spot onthe patient's skin, the fluorescence signal will then increasesignificantly, relative to the signal produced when the aperture isadjacent only to skin that has not been stained (i.e.,autofluorescence). Subtraction of the autofluorescence signal from thetotal signal provides a final signal, the value of which should increaseas the skin-spot and aperture become better aligned. If there are morethan one apertures (49 in FIG. 3D), each of them may have their own LED,dichroic mirror, filter, and photodetector, in which case, the sum ofthe electronically-detected signals corresponding to the differentspots' fluorescence indicates whether all the skin-spots and apertureshave been aligned. Alternatively, a single LED, dichroic mirror, filter,and photodetector may be used, in which case a Y-shaped optical fibermay be used to join two external apertures (top of the Y) to form asingle window (bottom of the Y).

As shown in FIG. 3D, the fluorescence signal is provided to the controlunit 330 in FIG. 1 and FIG. 5. The control unit may then use that signalto display within the patient interface computer program the extent towhich the stimulator has been optimally positioned. The control unit mayalso be configured to disable stimulation of the vagus nerve unlessalignment of the skin-spots and apertures has been detected. Forexample, use of the fluorescent spot alignment signal is one method totest whether the patient is attempting to stimulate the vagus nerve onthe intended side of the neck. It is understood, however, that thefluorescence alignment method described above may not be suitable forall patients, particularly patients having necks that are wrinkled orthat contain large amounts of fatty tissue.

Another method for testing whether the patient is attempting tostimulate the vagus nerve on the intended side of the neck makes use ofminiature three-axis accelerometers (possibly with combined gyroscopes)that are embedded in the body of the stimulator (for example, ModelLSM330DL from STMicroelectronics, 750 Canyon Dr #300 Coppell, Tex.75019). Such an accelerometer is situated in each of the two simulatorheads (31 in FIG. 3), and another accelerometer is situated in thevicinity of the bottom of the stimulator (38 in FIG. 3). Theaccelerometers will be providing positional data even when thestimulator is attached to the docking station, so that the orientationof the stimulator with respect to gravity is known from that data, andinitial positions of the accelerometers with respect to one another arealso known from the structure of the stimulator. Inferences that may bemade, as described below, may then be made by a computer program that isimplemented by a microprocessor that is situated within the stimulatorhousing. The patient will be facing the docking station when he or sheremoves the stimulator from the docking station, thereby definingdirections left and right as viewed by the patient. As the patient holdsthe stimulator in a hand and even walks about the room, relativepositions of the stimulator heads retain their left and right aspectsbecause the stimulator housing and patient with the stimulator in handmove together. Thus, by integrating the accelerations provided by theaccelerometers to infer the present location of the accelerometers, thedirections left and right may also be inferred, after translocation androtation of the initial accelerometer axes into the present axes. Sowhen the patient begins the stimulation as indicated by rotation of theamplitude thumbwheel (34 in FIG. 3), it may be determined that thestimulator heads with respect to the base of the stimulator are pointinggenerally in the leftward direction (i.e., right vagus nerve stimulatedis being attempted) or generally in the rightward direction (i.e., leftvagus nerve stimulation is being attempted).

The left versus right inference described in the previous paragraph maybe confirmed by the stimulator's computer program, by examining thepositions of the stimulator heads with respect to one another, asindicated by the accelerometer data. The stimulator shown in FIG. 3A hasa thumbwheel that could be rotated by either the left or right handthumbs. If the wheel is being rotated by the right hand thumb (rightvagus nerve stimulated is being attempted), a particular stimulator headwill be on top. However, if the wheel is being rotated by the left handthumb (left vagus nerve stimulated is being attempted), the otherstimulator head will be on top. Alternatively, the decision by thestimulator's computer program as to which hand is being used to hold thestimulator may be made by measuring capacitance on the outside of thestimulator body, which may distinguish fingers wrapped around the deviceversus the ball of a thumb [Raphael WIMMER and Sebastian Boring.HandSense: discriminating different ways of grasping and holding atangible user interface. Proceedings of the 3rd International Conferenceon Tangible and Embedded Interaction, pp. 359-362. ACM New York, N.Y.,2009]. If the combined decision of the stimulator is that the patient isattempting to stimulate the wrong vagus nerve, the stimulation will bewithheld, and the stimulator may then communicate with the patient viathe interface computer program (in the mobile phone or laptop computer)to alert the patient of that fact and possibly allow for overriding thatdecision.

Assume now that the vagus nerve is being stimulated on the correct sideof the neck and that the stimulator position is optimal. The patient maythen attempt to adjust the amplitude of the stimulation. If thestimulator is being held in place by hand, it is likely that there maybe inadvertent fluctuating movement of the stimulator, due for exampleto neck movement during respiration. Such relative movements will affectthe effectiveness of the stimulation. However, they may be monitored byaccelerometers in the stimulator, which may be transmitted as movementdata from the stimulator to the patient interface computer program (inthe mobile phone or laptop computer). The movements may also beaccompanied by fluctuations in the spot-alignment fluorescence signal.By watching a graphical display of the relative movements shown by thepatient interface computer program, the patient may use that display inan attempt to deliberately minimize the movements. Otherwise, thepatient may attempt to adjust the amplitude of the stimulator ascompensation for movement of the stimulator away from its optimumposition. In a section that follows, it is described how the stimulatoritself may modulate the amplitude of the stimulation in order to makesuch compensations.

The stimulation waveform may be synthesized within the stimulatorhousing, or it may be synthesized in the docking station or some othercomponent of the system and transmitted to the stimulator housing. Notethat the latter is generally different than the transmission of apre-recorded waveform signal [U.S. Pat. No. 8,112,154, entitled Systemsand methods for neuromodulation using pre-recorded waveforms, to REZAIet al]. During the stimulation session, the patient may also testwhether the vagus nerve is in fact being stimulated. Several of the testmethods described in previous sections are well suited to implementationwithin the patient interface device, for example, as a mobile phone app.For the laryngeal tests, the patient will perform the rising vowel test,speaking into the microphone of the mobile phone held at a fixeddistance from the patient's mouth. The app will then digitize the speechand process it as disclosed above, or transmit the speech data forprocessing to the docking station, or to computers on the internet.Similarly, the electroglottographic and/or laryngeal electromyographicdata will be transmitted from the stimulator housing for processing,with all test results of the processing transmitted back to theinterface device for viewing by the patient.

For the pupil diameter test, the camera of the mobile phone will befocused onto one or both eyes of the patient, the image of which will beprocessed to determine pupil diameter, latency, and asymmetry indices.Alternatively, the mobile phone is attached by cable to a camera,preferably an infrared camera, images from which may be transferred fromthe camera to the mobile phone. Images of the patient's pupil(s) fromtaken by either the mobile phone or auxiliary camera will also beprocessed within the app or transmitted for processing to the dockingstation, or to computers on the internet. Again, all results of theprocessing will be transmitted back to the interface device for viewingby the patient. Such results will also be transmitted to the patient'scaregiver for review. As described in the next section, the patient'sheart rate may be measured with sensors that do not even require that anECG electrode be attached to the patient's skin. The sensors may insteadbe situated within the patient's clothing. In any case, the measuredindividual heart beats provide the raw data needed to calculate theheart rate variability indices that were described in a previoussection. The electrodermal test would, however, require that theelectrodermal sensor(s) be attached to the patient's skin. Such sensorsmay also have built-in wireless transmission capability. The rawelectrodermal data will then be transmitted wirelessly to the dockingstation, which will process the data or transmit the data to some otherdevice for processing. The patient will then view the results of thesetests and adjust the amplitude of the stimulator accordingly.

Stimulation by the patient will then continue until the batteries of thestimulator are depleted, or the patient decides to terminate thestimulation session. At that point, the patient will insert thestimulator housing back into the docking station, whereupon thestimulator will transfer to the docking station data that itsmicroprocessor has caused to be stored regarding the stimulation session(e.g., stimulation amplitude as a function of time and information aboutmovements of the device during the session, duration of the stimulation,etc.). Such information will then be transmitted to and displayed by thepatient interface computer program (in the mobile phone or laptopcomputer), which will subsequently ask the patient questions regardingthe effectiveness of the stimulation. Such questions may be in regardsto the post-stimulation severity of the headache, whether the severitydecreased gradually or abruptly during the course of the stimulation,and whether anything unusual or noteworthy occurred during thestimulation. All such post-stimulation data will also be delivered overthe internet by the patient interface computer program to thephysician's computer for review and possible adjustment of the algorithmthat is used to select stimulation parameters and regimens. It isunderstood that the physician will adjust the algorithm based not onlyon the experience of each individual patient, but on the experience ofall patients collectively so as to improve effectiveness of thestimulator's use, for example, by identifying characteristics of mostand least responsive patients.

Before logging off of the interface computer program, the patient mayalso review database records and summaries about all previous treatmentsessions, so as to make his or her own judgment about treatmentprogress. If the stimulation was part of a prophylactic treatmentregimen that was prescribed by the patient's physician, the patientinterface computer program will remind the patient about the schedulefor the upcoming self-treatment sessions and allow for a rescheduling ifnecessary.

For some patients, the stimulation may be performed for as little asfive minutes, but it may also be for up to 30 minutes or longer. Thetreatment is generally performed once or twice daily or several times aweek, for 12 weeks or longer before a decision is made as to whether tocontinue the treatment. For patients experiencing intermittent symptoms,the treatment may be performed only when the patient is symptomatic.However, it is understood that parameters of the stimulation protocolmay be varied in response to heterogeneity in the pathophysiology ofpatients. Different stimulation parameters may also be used as thecourse of the patient's condition changes.

In some embodiments of the invention, pairing of vagus nerve stimulationmay be with a additional sensory stimulation. The paired sensorystimulation may be bright light, sound, tactile stimulation, orelectrical stimulation of the tongue to simulate odor/taste, e.g.,pulsating with the same frequency as the vagus nerve electricalstimulation. The sensory stimulation may be intended for the measurementof an evoked potential. But the rationale for paired sensory stimulationmay also be the same as simultaneous, paired stimulation of both leftand right vagus nerves, namely, that the pair of signals interactingwith one another in the brain may result in the formation of larger andmore coherent neural ensembles than the neural ensembles associated withthe individual signals, thereby enhancing the therapeutic effect. Thispairing may be considered especially when some such correspondingsensory circuit of the brain is thought to be partly responsible fortriggering the migraine headache.

Brain imaging methods may be used for reasons other than simplydemonstrating that the vagus nerve is being stimulated. Selection ofstimulation parameters to preferentially stimulate particular regions ofthe brain may be done empirically, wherein a set of stimulationparameters are chosen, and the responsive region of the brain ismeasured using fMRI or a related imaging method [CHAE J H, Nahas Z,Lomarev M, Denslow S, Lorberbaum J P, Bohning D E, George M S. A reviewof functional neuroimaging studies of vagus nerve stimulation (VNS). JPsychiatr Res. 37(6, 2003):443-455; CONWAY C R, Sheline Y I, Chibnall JT, George M S, Fletcher J W, Mintun M A. Cerebral blood flow changesduring vagus nerve stimulation for depression. Psychiatry Res. 146(2,2006)179-84]. Thus, by performing the imaging with different sets ofstimulation parameters, a database may be constructed, such that theinverse problem of selecting parameters to match a particular brainregion may be solved by consulting the database.

The individualized selection of parameters for the nerve stimulationprotocol may based on trial and error in order to obtain a beneficialresponse without the sensation of skin pain or muscle twitches.Alternatively, the selection of parameter values may involve tuning asunderstood in control theory, as described below. It is understood thatparameters may also be varied randomly in order to simulate normalphysiological variability, thereby possibly inducing a beneficialresponse in the patient [Buchman T G. Nonlinear dynamics, complexsystems, and the pathobiology of critical illness. Curr Opin Crit Care10(5, 2004):378-82].

Use of Control Theory Methods to Improve Treatment of IndividualPatients

The vagus nerve stimulation may employ methods of control theory (e.g.,feedback) in an attempt to compensate for motion of the stimulatorrelative to the vagus nerve and to avoid potentially dangeroussituations such as excessive heart rate. Thus, with these methods, theparameters of the vagus nerve stimulation may be changed automatically,depending on environmental signals or on physiological measurements thatare made, in attempt to maintain the values of the physiological signalswithin predetermined ranges.

When stimulating the vagus nerve, motion variability may often beattributable to the patient's breathing, which involves contraction andassociated change in geometry of the sternocleidomastoid muscle that issituated close to the vagus nerve (identified as 65 in FIG. 8).Modulation of the stimulator amplitude to compensate for thisvariability may be accomplished by measuring the patient's respiratoryphase, or more directly by measuring movement of the stimulator, thenusing controllers (e.g., PID controllers) that are known in the art ofcontrol theory, as now described.

FIG. 9 is a control theory representation of the disclosed vagus nervestimulation methods. The “System” (patient) receives input from the“Environment.” For example, the environment would include ambienttemperature, light, and sound, all of which may be triggers of amigraine attack. If the “System” is defined to be only a particularphysiological component of the patient, the “Environment” may also beconsidered to include physiological systems of the patient that are notincluded in the “System”. Thus, if some physiological component caninfluence the behavior of another physiological component of thepatient, but not vice versa, the former component could be part of theenvironment and the latter could be part of the system. On the otherhand, if it is intended to control the former component to influence thelatter component, then both components should be considered part of the“System.”

The System also receives input from the “Controller”, which in this casemay comprise the vagus nerve stimulation device, as well as electroniccomponents that may be used to select or set parameters for thestimulation protocol (amplitude, frequency, pulse width, burst number,etc.) or alert the patient as to the need to use or adjust thestimulator (i.e., an alarm). For example, the controller may comprisethe control unit 330 in FIG. 1. Feedback in the schema shown in FIG. 9is possible because physiological measurements of the System are madeusing sensors. Thus, the values of variables of the system that could bemeasured define the system's state (“the System Output”). As a practicalmatter, only some of those measurements are actually made, and theyrepresent the “Sensed Physiological Input” to the Controller.

The preferred sensors will include ones ordinarily used for ambulatorymonitoring. For example, the sensors may comprise those used inconventional Holter and bedside monitoring applications, for monitoringheart rate and variability, ECG, respiration depth and rate, coretemperature, hydration, blood pressure, brain function, oxygenation,skin impedance, and skin temperature. The sensors may be embedded ingarments or placed in sports wristwatches, as currently used in programsthat monitor the physiological status of soldiers [G. A. SHAW, A. M.Siegel, G. Zogbi, and T. P. Opar. Warfighter physiological andenvironmental monitoring: a study for the U.S. Army Research Institutein Environmental Medicine and the Soldier Systems Center. MIT LincolnLaboratory, Lexington Mass. 1 Nov. 2004, pp. 1-141]. The ECG sensorsshould be adapted to the automatic extraction and analysis of particularfeatures of the ECG, for example, indices of P-wave morphology, as wellas heart rate variability indices of parasympathetic and sympathetictone. Measurement of respiration using noninvasive inductiveplethysmography, mercury in silastic strain gauges or impedancepneumography is particularly advised, in order to account for theeffects of respiration on the heart. A noninvasive accelerometer mayalso be included among the ambulatory sensors, in order to identifymotion artifacts. An event marker may also be included in order for thepatient to mark relevant circumstances and sensations.

For brain monitoring, the sensors may comprise ambulatory EEG sensors[CASSON A, Yates D, Smith S, Duncan J, Rodriguez-Villegas E. Wearableelectroencephalography. What is it, why is it needed, and what does itentail? IEEE Eng Med Biol Mag. 29(3, 2010):44-56] or optical topographysystems for mapping prefrontal cortex activation [Atsumori H, Kiguchi M,Obata A, Sato H, Katura T, Funane T, Maki A. Development of wearableoptical topography system for mapping the prefrontal cortex activation.Rev Sci Instrum. 2009 April; 80(4):043704]. Signal processing methods,comprising not only the application of conventional linear filters tothe raw EEG data, but also the nearly real-time extraction of non-linearsignal features from the data, may be considered to be a part of the EEGmonitoring [D. Puthankattil SUBHA, Paul K. Joseph, Rajendra Acharya U,and Choo Min Lim. EEG signal analysis: A survey. J Med Syst 34(2010)195-212]. Such features would include EEG bands (e.g., delta,theta, alpha, beta).

Detection of the phase of respiration may be performed non-invasively byadhering a thermistor or thermocouple probe to the patient's cheek so asto position the probe at the nasal orifice. Strain gauge signals frombelts strapped around the chest, as well as inductive plethysmographyand impedance pneumography, are also used traditionally tonon-invasively generate a signal that rises and falls as a function ofthe phase of respiration. Respiratory phase may also be inferred frommovement of the sternocleidomastoid muscle that also causes movement ofthe vagus nerve stimulator during breathing, measured usingaccelerometers attached to the vagus nerve stimulator, as describedbelow. After digitizing such signals, the phase of respiration may bedetermined using software such as “puka”, which is part ofPhysioToolkit, a large published library of open source software anduser manuals that are used to process and display a wide range ofphysiological signals [GOLDBERGER A L, Amaral L A N, Glass L, HausdorffJ M, Ivanov P Ch, Mark R G, Mietus J E, Moody G B, Peng C K, Stanley HE. PhysioBank, PhysioToolkit, and PhysioNet: Components of a NewResearch Resource for Complex Physiologic Signals. Circulation 101(23,2000):e215-e220] available from PhysioNet, M.I.T. Room E25-505A, 77Massachusetts Avenue, Cambridge, Mass. 02139]. In one embodiment of thepresent invention, the control unit 330 contains an analog-to-digitalconverter to receive such analog respiratory signals, and software forthe analysis of the digitized respiratory waveform resides within thecontrol unit 330. That software extracts turning points within therespiratory waveform, such as end-expiration and end-inspiration, andforecasts future turning-points, based upon the frequency with whichwaveforms from previous breaths match a partial waveform for the currentbreath. The control unit 330 then controls the impulse generator 310,for example, to stimulate the selected nerve only during a selectedphase of respiration, such as all of inspiration or only the firstsecond of inspiration, or only the expected middle half of inspiration.In other embodiments of the invention, the physiological orenvironmental signals are transmitted wirelessly to the controller, asshown in FIG. 5. Some such signals may be received by the dockingstation (e.g., ambient sound signals) and other may be received withinthe stimulator housing (e.g., motion signals).

It may be therapeutically advantageous to program the control unit 330to control the impulse generator 310 in such a way as to temporallymodulate stimulation by the electrodes, depending on the phase of thepatient's respiration. In patent application JP2008/081479A, entitledVagus nerve stimulation system, to YOSHIHOTO, a system is also describedfor keeping the heart rate within safe limits. When the heart rate istoo high, that system stimulates a patient's vagus nerve, and when theheart rate is too low, that system tries to achieve stabilization of theheart rate by stimulating the heart itself, rather than use differentparameters to stimulate the vagus nerve. In that disclosure, vagalstimulation uses an electrode, which is described as either a surfaceelectrode applied to the body surface or an electrode introduced to thevicinity of the vagus nerve via a hypodermic needle. That disclosure isunrelated to the headache problems that are addressed here, but it doesconsider stimulation during particular phases of the respiratory cycle,for the following reason. Because the vagus nerve is near the phrenicnerve, Yoshihoto indicates that the phrenic nerve will sometimes beelectrically stimulated along with the vagus nerve. The presentapplicants have not experienced this problem, so the problem may be oneof a misplaced electrode. In any case, the phrenic nerve controlsmuscular movement of the diaphragm, so consequently, stimulation of thephrenic nerve causes the patient to hiccup or experience irregularmovement of the diaphragm, or otherwise experience discomfort. Tominimize the effects of irregular diaphragm movement, Yoshihoto's systemis designed to stimulate the phrenic nerve (and possibly co-stimulatethe vagus nerve) only during the inspiration phase of the respiratorycycle and not during expiration. Furthermore, the system is designed togradually increase and then decrease the magnitude of the electricalstimulation during inspiration (notably amplitude and stimulus rate) soas to make stimulation of the phrenic nerve and diaphragm gradual.

Furthermore, as an option in the present invention, parameters of thestimulation may be modulated by the control unit 330 to control theimpulse generator 310 in such a way as to temporally modulatestimulation by the electrodes, so as to achieve and maintain the heartrate within safe or desired limits. In that case, the parameters of thestimulation are individually raised or lowered in increments (power,frequency, etc.), and the effect as an increased, unchanged, ordecreased heart rate is stored in the memory of the control unit 330.When the heart rate changes to a value outside the specified range, thecontrol unit 330 automatically resets the parameters to values that hadbeen recorded to produce a heart rate within that range, or if no heartrate within that range has yet been achieved, it increases or decreasesparameter values in the direction that previously acquired data indicatewould change the heart rate in the direction towards a heart rate in thedesired range. Similarly, the arterial blood pressure is also recordednon-invasively in an embodiment of the invention, and as describedabove, the control unit 330 extracts the systolic, diastolic, and meanarterial blood pressure from the blood pressure waveform. The controlunit 330 will then control the impulse generator 310 in such a way as totemporally modulate nerve stimulation by the electrodes, in such a wayas to achieve and maintain the blood pressure within predetermined safeor desired limits, by the same method that was indicated above for theheart rate.

Let the measured output variables of the system in FIG. 9 be denoted byYi (i=1 to Q); let the desired (reference or setpoint) values of yi bedenoted by ri and let the controller's input to the system consist ofvariables u_(i) (j=1 to P). The objective is for a controller to selectthe input u; in such a way that the output variables (or a subset ofthem) closely follows the reference signals r_(i), i.e., the controlerror e_(i)=r_(i)−y_(i) is small, even if there is environmental inputor noise to the system. Consider the error function e_(i)=r_(i)−y_(i) tobe the sensed physiological input to the controller in FIG. 9 (i.e., thereference signals are integral to the controller, which subtracts themeasured system values from them to construct the control error signal).The controller will also receive a set of measured environmental signalsv_(k) (k=1 to R), which also act upon the system as shown in FIG. 9.

The functional form of the system's input u(t) is constrained to be asshown in FIGS. 2B and 2C. Ordinarily, a parameter that needs adjustingis the one associated with the amplitude of the signal shown in FIG. 2A.As a first example of the use of feedback to control the system,consider the problem of adjusting the input u(t) from the vagus nervestimulator (i.e., output from the controller) in order to compensate formotion artifacts.

Nerve activation is generally a function of the second spatialderivative of the extracellular potential along the nerve's axon, whichwould be changing as the position of the stimulator varies relative tothe axon [F. RATTAY. The basic mechanism for the electrical stimulationof the nervous system. Neuroscience 89 (2, 1999):335-346]. Such motionartifact can be due to movement by the patient (e.g., neck movement) ormovement within the patient (e.g. sternocleidomastoid muscle contractionassociated with respiration), or it can be due to movement of thestimulator relative to the body (slippage or drift). Thus, one expectsthat because of such undesired or unavoidable motion, there will usuallybe some error (e=r−y) in the intended (r) versus actual (y) nervestimulation amplitude that needs continuous adjustment.

Accelerometers can be used to detect all these types of movement, usingfor example, Model LSM330DL from STMicroelectronics, 750 Canyon Dr #300Coppell, Tex. 75019. In one embodiment, one or more accelerometer isattached to the patient's neck, and one or more accelerometer isattached to the head(s) of the stimulator in the vicinity of where thestimulator contacts the patient. Because the temporally integratedoutputs of the accelerometers provide a measurement of the currentposition of each accelerometer, the combined accelerometer outputs makeit possible to measure any movement of the stimulator relative to theunderlying tissue.

The location of the vagus nerve underlying the stimulator may bedetermined preliminarily by placing an ultrasound probe at the locationwhere the center of the stimulator will be placed, as described in aprevious section. As part of the preliminary protocol, the patient withaccelerometers attached is then instructed or helped to perform neckmovements, breathe deeply so as to contract the sternocleidomastoidmuscle, and generally simulate possible motion that may accompanyprolonged stimulation with the stimulator. This would include possibleslippage or movement of the stimulator relative to an initial positionon the patient's neck. While these movements are being performed, theaccelerometers are acquiring position information, and the correspondinglocation of the vagus nerve is determined from the ultrasound image.With these preliminary data, it is then possible to infer the locationof the vagus nerve relative to the stimulator, given only theaccelerometer data during a stimulation session, by interpolatingbetween the previously acquired vagus nerve position data as a functionof accelerometer position data.

For any given position of the stimulator relative to the vagus nerve, itis also possible to infer the amplitude of the electric field that itproduces in the vicinity of the vagus nerve. This is done by calculationor by measuring the electric field that is produced by the stimulator asa function of depth and position within a phantom that simulates therelevant bodily tissue [Francis Marion MOORE. Electrical Stimulation forpain suppression: mathematical and physical models. Thesis, School ofEngineering, Cornell University, 2007; Bartosz SAWICKI, Robert Szmuro,Przemyslaw Ponecki, Jacek Starzy ski, Stanisaw Wincenciak, Andrzej Rysz.Mathematical Modelling of Vagus Nerve Stimulation. pp. 92-97 in:Krawczyk, A. Electromagnetic Field, Health and Environment: Proceedingsof EHE'07. Amsterdam, IOS Press, 2008]. Thus, in order to compensate formovement, the controller may increase or decrease the amplitude of theoutput from the stimulator (u) in proportion to the inferred deviationof the amplitude of the electric field in the vicinity of the vagusnerve, relative to its desired value.

For present purposes, no distinction is made between a system outputvariable and a variable representing the state of the system. Then, astate-space representation, or model, of the system consists of a set offirst order differential equations of the form dy_(i)/dt=F_(i)(t,{y_(i)},{u_(j)},{v_(k)};{r_(i)), where t is time andwhere in general, the rate of change of each variable y_(i) is afunction (F_(i)) of many other output variables as well as the input andenvironmental signals.

Classical control theory is concerned with situations in which thefunctional form of F_(i) is as a linear combination of the state andinput variables, but in which coefficients of the linear terms are notnecessarily known in advance. In this linear case, the differentialequations may be solved with linear transform (e.g., Laplace transform)methods, which convert the differential equations into algebraicequations for straightforward solution. Commercial versions of PIDcontrollers are available, and they are used in 90% of all controlapplications.

Optimal selection of the parameters of the controller could be throughcalculation, if the coefficients of the corresponding state differentialequation were known in advance. However, they are ordinarily not known,so selection of the controller parameters (tuning) is accomplished byexperiments in which the error e either is or is not used to form thesystem input (respectively, closed loop or open loop experiments). In anopen loop experiment, the input is increased in a step (or random binarysequence of steps), and the system response is measured. In a closedloop experiment, the integral and derivative gains are set to zero, theproportional gain is increased until the system starts to oscillate, andthe period of oscillation is measured. Depending on whether theexperiment is open or closed loop, the selection of PID parameter valuesmay then be selected according to rules that were described initially byZiegler and Nichols. There are also many improved versions of tuningrules, including some that can be implemented automatically by thecontroller [LI, Y., Ang, K. H. and Chong, G. C. Y. Patents, software andhardware for PID control: an overview and analysis of the current art.IEEE Control Systems Magazine, 26 (1, 2006): 42-54; Karl Johan.ANG.strom & Richard M. Murray. Feedback Systems: An Introduction forScientists and Engineers. Princeton N.J.:Princeton University Press,2008; Finn HAUGEN. Tuning of PID controllers (Chapter 10) In: BasicDynamics and Control. 2009. ISBN 978-82-91748-13-9. TechTeach,Enggravhogda 45, N-3711 Skien, Norway. http://techteach.no., pp.129-155; Dingyu XUE, YangQuan Chen, Derek P. Atherton. PID controllerdesign (Chapter 6), In: Linear Feedback Control: Analysis and Designwith MATLAB. Society for Industrial and Applied Mathematics (SIAM).3600Market Street, 6th Floor, Philadelphia, Pa. (2007), pp. 183-235; JanJANTZEN, Tuning Of Fuzzy PID Controllers, Technical University ofDenmark, report 98-H 871, Sep. 30, 1998].

The controller shown in FIG. 9 may also make use of feed-forward methods[Coleman BROSILOW, Babu Joseph. Feedforward Control (Chapter 9) In:Techniques of Model-Based Control. Upper Saddle River, N.J.: PrenticeHall PTR, 2002. pp., 221-240]. Thus, the controller in FIG. 9 may be atype of predictive controller, methods for which have been developed inother contexts as well, such as when a model of the system is used tocalculate future outputs of the system, with the objective of choosingamong possible inputs so as to optimize a criterion that is based onfuture values of the system's output variables.

A disclosure of the use of such feedback and feedforward methods toforecast and avert the onset of an imminent migraine attack was made inthe co-pending, commonly assigned application U.S. Ser. No. 13/357,010(publication US 2012/0185020), entitled Nerve stimulation methods foraverting imminent onset or episode of a disease, to SIMON et al, whichis hereby incorporated by reference.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as defined by the appended claims.

What is claimed is:
 1. A method for treating a medical condition of apatient, the method comprising: contacting an outer skin surface of apatient with a contact surface of a nerve stimulator; generating anelectrical impulse; transmitting, as the contact surface contacts theouter skin surface, the electrical impulse from the nerve stimulator,non-invasively through the outer skin surface, to a nerve such that theelectrical impulse modulates the nerve; measuring a physiologicalresponse of the patient to the nerve being modulated based on theelectrical impulse being transmitted to the nerve; detecting, based onthe physiological response, whether a stimulation level of theelectrical impulse sufficiently modulates the nerve to treat the medicalcondition; and adjusting a position of the contact surface on the outerskin surface based on the physiological response being measured.
 2. Themethod of claim 1, wherein the nerve stimulator comprises a housinghosting the contact surface, wherein the electrical impulse is generatedwithin the housing.
 3. The method of claim 1, wherein measuring thephysiological response comprises measuring a blood flow associated withthe nerve.
 4. The method of claim 1, wherein the nerve is at least oneof a vagus nerve, a cranial nerve, a peripheral nerve, or a spinalnerve.
 5. The method of claim 1, wherein measuring the physiologicalresponse comprises sensing a level of a biological marker within thepatient.
 6. The method of claim 1, wherein measuring the physiologicalresponse comprises measuring a property of at least one of a voice ofthe patient, a laryngeal electromyographic signal, or anelectroglottographic signal.
 7. The method of claim 1, wherein measuringthe physiological response comprises measuring a property of anautonomic nervous system of the patient.
 8. The method of claim 1,wherein measuring the physiological response comprises measuring atleast one of a vagal artery blood flow of the patient or a cerebralblood flow of the patient.
 9. The method of claim 1, wherein measuringthe physiological response comprises measuring a chemical within a bloodof the patient.
 10. The method of claim 1, further comprising adjustinga parameter of the electrical impulse based on the physiologicalresponse being measured, wherein the parameter comprises at least one ofan amplitude of the electrical impulse, a frequency of the electricalimpulse, a duration of the electrical impulse, or a waveform of theelectrical impulse.
 11. The method of claim 1, wherein the electricalimpulse comprises bursts of about 2 pulses per burst to about 20 pulsesper burst with each of the bursts having a frequency of about 1 burstper second to about 100 bursts per second and each of the pulses havinga duration of about 50 microseconds to about 1000 microseconds.
 12. Asystem for treating a medical condition of a patient, the systemcomprising: a stimulator including a contact surface that contacts anouter skin surface of a patient; an energy source that generates anelectric field such that an electric current is transmittednon-invasively from the contact surface through the outer skin surfaceto the nerve; a sensor for measuring a physiological response of thepatient to the nerve being modulated based on the electrical impulsebeing transmitted to the nerve; a device that detects a stimulationlevel of the nerve based on the physiological response; and a controllercoupled to the device, wherein the controller adjusts a position of thecontact surface on the outer skin surface based on the stimulationlevel.
 13. The system of claim 12, wherein the stimulator comprises ahousing hosting the contact surface, wherein the energy source ispositioned within the housing.
 14. The system of claim 12, wherein thesensor measures a blood flow associated with the nerve.
 15. The systemof claim 12, wherein the nerve is at least one of a vagus nerve of thepatient, a cranial nerve of the patient, a peripheral nerve of thepatient, or a spinal nerve of the patient.
 16. The system of claim 12,wherein the sensor detects a level of a biological marker within thepatient.
 17. The system of claim 12, wherein the sensor detects aproperty of an autonomic nervous system of the patient.
 18. The systemof claim 12, wherein the controller adjusts at least one of an amplitudeof the electric current, a frequency of the electric current, a durationof the electric current, or a waveform of the electric current.
 19. Thesystem of claim 12, wherein the electric current comprises bursts ofabout 2 pulses per burst to about 20 pulses per burst with each of thebursts having a frequency of about 1 burst per second to about 100bursts per second and each of the pulses having a duration of about 50microseconds to about 1000 microseconds.